Volume 178, Issue S1 p. S27-S156
THE CONCISE GUIDE TO PHARMACOLOGY 2021/22
Open Access

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors

Stephen P H Alexander

Stephen P H Alexander

School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH UK

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Arthur Christopoulos

Arthur Christopoulos

Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria 3052 Australia

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Anthony P Davenport

Anthony P Davenport

Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ UK

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Eamonn Kelly

Eamonn Kelly

School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD UK

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Alistair Mathie

Alistair Mathie

School of Engineering, Arts, Science and Technology, University of Suffolk, Ipswich, IP4 1QJ UK

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John A Peters

John A Peters

Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY UK

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Emma L Veale

Emma L Veale

Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB UK

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Jane F Armstrong

Jane F Armstrong

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD UK

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Elena Faccenda

Elena Faccenda

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD UK

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Simon D Harding

Simon D Harding

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD UK

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Adam J Pawson

Adam J Pawson

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD UK

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Christopher Southan

Christopher Southan

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD UK

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Jamie A Davies

Jamie A Davies

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD UK

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Maria Pia Abbracchio

Maria Pia Abbracchio

University of Milan, Milan, Italy

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Wayne Alexander

Wayne Alexander

Emory University, Atlanta, USA

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Khaled Al-hosaini

Khaled Al-hosaini

King Saud University, Riyadh, Kingdom of Saudi Arabia

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Magnus Bäck

Magnus Bäck

Karolinska University Hospital, Stockholm, Sweden

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Nicholas M. Barnes

Nicholas M. Barnes

University of Birmingham, Birmingham, UK

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Ross Bathgate

Ross Bathgate

Florey Institute of Neuroscience and Mental Health, Melbourne, Australia

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Jean-Martin Beaulieu

Jean-Martin Beaulieu

University of Toronto, Toronto, Canada

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Kenneth E. Bernstein

Kenneth E. Bernstein

Cedars-Sinai Medical Center, Los Angeles, USA

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Bernhard Bettler

Bernhard Bettler

University of Basel, Basel, Switzerland

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Nigel J.M. Birdsall

Nigel J.M. Birdsall

The Francis Crick Institute, London, UK

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Victoria Blaho

Victoria Blaho

Sanford Burnham Prebys Medical Discovery Institute, La Jolla, USA

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Francois Boulay

Francois Boulay

University of Grenoble Alpes, Grenoble, France

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Corinne Bousquet

Corinne Bousquet

French Institute of Health and Medical Research(INSERM), Toulouse, France

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Hans Bräuner-Osborne

Hans Bräuner-Osborne

University of Copenhagen, Copenhagen, Denmark

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Geoffrey Burnstock

Geoffrey Burnstock

University College London, Melbourne, Australia

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Girolamo Caló

Girolamo Caló

University of Padova, Padova, Italy

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Justo P. Castaño

Justo P. Castaño

University of Córdoba, Córdoba, Spain

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Kevin J. Catt

Kevin J. Catt

National Institute of Health, Bethesda, USA

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Stefania Ceruti

Stefania Ceruti

University of Milan, Milan, Italy

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Paul ChazotNan Chiang

Nan Chiang

Harvard University, Boston, MA, USA

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Bice Chini

Bice Chini

University of Milan Bicocca, Vedano al Lambro, Italy

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Jerold Chun

Jerold Chun

University of California San Diego, La Jolla, USA

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Antonia Cianciulli

Antonia Cianciulli

University of Bari, Bari, Italy

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Olivier Civelli

Olivier Civelli

University of California Irvine, Irvine, USA

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Lucie H. Clapp

Lucie H. Clapp

University College London, London, UK

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Réjean Couture

Réjean Couture

University of Montréal, Montréal, Canada

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Zsolt Csaba

Zsolt Csaba

French Institute of Health and Medical Research(INSERM), Paris, France

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Claes Dahlgren

Claes Dahlgren

University of Gothenburg, Gothenburg, Sweden

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Gordon DentKhuraijam Dhanachandra Singh

Khuraijam Dhanachandra Singh

Cleveland Clinic Lerner Research Institute, Cleveland, USA

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Steven D. Douglas

Steven D. Douglas

University of Pennsylvania, Pennsylvania, USA

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Pascal Dournaud

Pascal Dournaud

French Institute of Health and Medical Research(INSERM), Paris, France

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Satoru Eguchi

Satoru Eguchi

Temple University, Philadelphia, USA

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Emanuel Escher

Emanuel Escher

University of Sherbrooke, Sherbrooke, Canada

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Edward J. Filardo

Edward J. Filardo

University of Iowa, Iowa City, USA

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Tung Fong

Tung Fong

Labcorp Drug Development, Somerset, USA

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Marta Fumagalli

Marta Fumagalli

University of Milan, Milan, Italy

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Raul R Gainetdinov

Raul R Gainetdinov

Saint Petersburg State University, Saint-Petersburg, Russia

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Marc de Gasparo

Marc de Gasparo

MG Consulting Co, Basel, Switzerland

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Craig Gerard

Craig Gerard

Harvard University, Boston, MA, USA

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Marvin Gershengorn

Marvin Gershengorn

National Institute of Health, Bethesda, USA

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Fernand Gobeil

Fernand Gobeil

University of Sherbrooke, Sherbrooke, Canada

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Theodore L. Goodfriend

Theodore L. Goodfriend

University of Wisconsin, Madison, USA

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Cyril Goudet

Cyril Goudet

French National Centre for Scientific Research, Montpellier, France

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Karen J. Gregory

Karen J. Gregory

Monash University, Parkville, Australia

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Andrew L. Gundlach

Andrew L. Gundlach

Florey Institute of Neuroscience and Mental Health, Melbourne, Australia

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Jörg Hamann

Jörg Hamann

Amsterdam University, Amsterdam, The Netherlands

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Julien Hanson

Julien Hanson

University of Liège, Liège, Belgium

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Richard L. Hauger

Richard L. Hauger

University of California San Diego, La Jolla, USA

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Debbie L. Hay

Debbie L. Hay

University of Otago, Dunedin, New Zealand

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Akos Heinemann

Akos Heinemann

Medical University of Graz, Graz, Austria

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Morley D. Hollenberg

Morley D. Hollenberg

University of Calgary, Calgary, Canada

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Nicholas D. Holliday

Nicholas D. Holliday

University of Nottingham, Nottingham, UK

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Mastgugu Horiuchi

Mastgugu Horiuchi

Ehime University, Ehime, Japan

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Daniel Hoyer

Daniel Hoyer

University of Melbourne, Melbourne, Australia

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László Hunyady

László Hunyady

Semmelweis University, Budapest, Hungary

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Ahsan Husain

Ahsan Husain

Emory University, Birmingham, USA

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Adriaan P. IJzerman

Adriaan P. IJzerman

Leiden University, Leiden, The Netherlands

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Tadashi Inagami

Tadashi Inagami

Vanderbilt University, Nashville, USA

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Kenneth A. Jacobson

Kenneth A. Jacobson

National Institute of Health, Bethesda, USA

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Robert T. Jensen

Robert T. Jensen

National Institute of Health, Bethesda, USA

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Ralf Jockers

Ralf Jockers

French Institute of Health and Medical Research(INSERM), Paris, France

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Deepa Jonnalagadda

Deepa Jonnalagadda

Sanford Burnham Prebys Medical Discovery Institute, La Jolla, USA

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Sadashiva Karnik

Sadashiva Karnik

Lerner Research Institute, Cleveland, USA

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Klemens Kaupmann

Klemens Kaupmann

Novartis, Basel, Switzerland

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Jacqueline Kemp

Jacqueline Kemp

Cleveland Clinic Lerner Research Institute, Cleveland, USA

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Charles Kennedy

Charles Kennedy

Strathclyde University, Glasgow, UK

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Yasuyuki Kihara

Yasuyuki Kihara

Sanford Burnham Prebys Medical Discovery Institute, La Jolla, USA

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Takio Kitazawa

Takio Kitazawa

Rakuno Gakuen University, Ebetsu, Japan

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Pawel Kozielewicz

Pawel Kozielewicz

Karolinska Institute, Stockholm, Sweden

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Hans-Jürgen Kreienkamp

Hans-Jürgen Kreienkamp

University of Hamburg, Hamburg, Germany

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Jyrki P. Kukkonen

Jyrki P. Kukkonen

University of Helsinki, Helsinki, Finland

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Tobias Langenhan

Tobias Langenhan

Leipzig University, Leipzig, Germany

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Katie Leach

Katie Leach

Monash University, Parkville, Australia

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Davide Lecca

Davide Lecca

University of Milan, Milan, Italy

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John D. Lee

John D. Lee

University of Queensland, Brisbane, Australia

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Susan E. Leeman

Susan E. Leeman

Boston University, Boston, MA, USA

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Jérôme Leprince

Jérôme Leprince

University of Rouen, Rouen, France

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Xaria X. Li

Xaria X. Li

University of Queensland, Brisbane, Australia

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Tom Lloyd Williams

Tom Lloyd Williams

University of Cambridge, Cambridge, UK

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Stephen J. Lolait

Stephen J. Lolait

University of Bristol, Bristol, UK

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Amelie Lupp

Amelie Lupp

Friedrich Schiller University Jena, Jena, Germany

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Robyn Macrae

Robyn Macrae

University of Cambridge, Cambridge, UK

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Janet Maguire

Janet Maguire

University of Cambridge, Cambridge, UK

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Jean Mazella

Jean Mazella

French National Centre for Scientific Research(CNRS), Valbonne, France

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Craig A. McArdle

Craig A. McArdle

University of Bristol, Bristol, UK

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Shlomo Melmed

Shlomo Melmed

Cedars-Sinai Medical Center, Los Angeles, USA

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Martin C. Michel

Martin C. Michel

Johannes Gutenberg University Mainz, Mainz, Germany

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Laurence J. Miller

Laurence J. Miller

Mayo Foundation for Medical Education and Research, Scottsdale, USA

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Vincenzo Mitolo

Vincenzo Mitolo

University of Bari, Bari, Italy

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Bernard Mouillac

Bernard Mouillac

French National Centre for Scientific Research, Montpellier, France

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Christa E. Müller

Christa E. Müller

University of Bonn, Bonn, Germany

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Philip Murphy

Philip Murphy

Edge Hill University, Bethesda, USA

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Jean-Louis Nahon

Jean-Louis Nahon

French National Centre for Scientific Research(CNRS), Valbonne, France

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Tony Ngo

Tony Ngo

Sanford Burnham Prebys Medical Discovery Institute, La Jolla, USA

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Xavier Norel

Xavier Norel

French Institute of Health and Medical Research(INSERM), Paris, France

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Duuamene Nyimanu

Duuamene Nyimanu

University of Cambridge, Cambridge, UK

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Anne-Marie O’Carroll

Anne-Marie O’Carroll

University of Bristol, Bristol, UK

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Stefan Offermanns

Stefan Offermanns

Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany

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Maria Antonietta Panaro

Maria Antonietta Panaro

University of Bari, Bari, Italy

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Marc Parmentier

Marc Parmentier

Free University of Brussels, Brussels, Belgium

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Roger G. Pertwee

Roger G. Pertwee

University of Aberdeen, Aberdeen, UK

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Jean-Philippe Pin

Jean-Philippe Pin

University of Montpellier, Montpellier, France

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Eric R. Prossnitz

Eric R. Prossnitz

University of New Mexico, Albuquerque, USA

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Mark Quinn

Montana State University, Bozeman, USA

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Rithwik Ramachandran

Rithwik Ramachandran

Western University, London, Canada

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Manisha Ray

Manisha Ray

Sanford Burnham Prebys Medical Discovery Institute, La Jolla, USA

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Rainer K. Reinscheid

Rainer K. Reinscheid

Friedrich Schiller University Jena, Jena, Germany

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Philippe Rondard

Philippe Rondard

University of Montpellier, Montpellier, France

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G. Enrico Rovati

G. Enrico Rovati

University of Milan, Milan, Italy

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Chiara Ruzza

Chiara Ruzza

University of Ferrara, Ferrara, Italy

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Gareth J. Sanger

Gareth J. Sanger

Queen Mary University of London, London, UK

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Torsten Schöneberg

Torsten Schöneberg

University of Leipzig, Leipzig, Germany

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Gunnar Schulte

Gunnar Schulte

Karolinska Institute, Stockholm, Sweden

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Stefan Schulz

Stefan Schulz

Friedrich Schiller University Jena, Jena, Germany

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Deborah L. Segaloff

Deborah L. Segaloff

University of Iowa, Iowa City, USA

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Charles N. Serhan

Harvard University, Boston, MA, USA

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Leigh A. Stoddart

Leigh A. Stoddart

University of Nottingham, Nottingham, UK

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Yukihiko Sugimoto

Yukihiko Sugimoto

Kumamoto University, Kumamoto, Japan

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Roger Summers

Monash University, Melbourne, Australia

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Valerie P. Tan

Valerie P. Tan

University of California San Diego, La Jolla, USA

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David Thal

Monash University, Melbourne, Australia

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Walter (Wally) Thomas

University of Queensland, Queensland, Australia

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Pieter B. M. W. M. Timmermans

Pieter B. M. W. M. Timmermans

Kosan Biosciences, Inc., San Francisco, CA, USA

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Kalyan Tirupula

Kalyan Tirupula

Cleveland Clinic Lerner Research Institute, Cleveland, USA

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Giovanni Tulipano

Giovanni Tulipano

University of Brescia, Brescia, Italy

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Hamiyet Unal

Hamiyet Unal

Cleveland Clinic, Cleveland, USA

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Thomas Unger

Thomas Unger

Maastricht University, Maastricht, The Netherlands

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Celine Valant

Celine Valant

Monash University, Melbourne, Australia

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Patrick Vanderheyden

Patrick Vanderheyden

Free University of Brussels, Brussels, Belgium

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David Vaudry

University of Rouen, Rouen, France

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Hubert Vaudry

Hubert Vaudry

University of Rouen, Rouen, France

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Jean-Pierre Vilardaga

Jean-Pierre Vilardaga

University of Pittsburgh, Pittsburgh, USA

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Christopher S. Walker

University of Auckland, Auckland, New Zealand

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Ji Ming Wang

National Institute of Health, Frederick, USA

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Donald T. Ward

Donald T. Ward

University of Manchester, Manchester, UK

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Hans-Jürgen Wester

Hans-Jürgen Wester

Technical University of Munich, Munich, Germany

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Gary B Willars

Gary B Willars

University of Leicester, Leicester, UK

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Trent M. Woodruff

University of Queensland, Brisbane, Australia

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Chengcan Yao

Chengcan Yao

University of Edinburgh, Edinburgh, UK

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Richard D. Ye

University of Illinois, Chicago, USA

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First published: 16 September 2021
Citations: 330

Abstract

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Conflict of interest

The authors state that there are no conflicts of interest to disclose.

Overview

G protein-coupled receptors (GPCRs) are the largest class of membrane proteins in the human genome. The term "7TM receptor" is commonly used interchangeably with "GPCR", although there are some receptors with seven transmembrane domains that do not signal through G proteins. GPCRs share a common architecture, each consisting of a single polypeptide with an extracellular N-terminus, an intracellular C-terminus and seven hydrophobic transmembrane domains (TM1-TM7) linked by three extracellular loops (ECL1-ECL3) and three intracellular loops (ICL1-ICL3). About 800 GPCRs have been identified in man, of which about half have sensory functions, mediating olfaction (˜400), taste (33), light perception (10) and pheromone signalling (5) [1617]. The remaining ˜350 non-sensory GPCRs mediate signalling by ligands that range in size from small molecules to peptides to large proteins; they are the targets for the majority of drugs in clinical usage [1797, 1948], although only a minority of these receptors are exploited therapeutically. The first classification scheme to be proposed for GPCRs [1221] divided them, on the basic of sequence homology, into six classes. These classes and their prototype members were as follows: Class A(rhodopsin-like), Class B (secretin receptor family), Class C (metabotropic glutamate), Class D (fungal mating pheromone receptors), Class E (cyclic AMP receptors) and Class F (frizzled/smoothened). Of these, classes D and E are not found in vertebrates. An alternative classification scheme "GRAFS" [2083] divides vertebrate GPCRs into five classes, overlapping with the A-F nomenclature, viz:

Glutamate family (class C), which includes metabotropic glutamate receptors, a calcium-sensing receptor and GABAB receptors, as well as three taste type 1 receptors and a family of pheromone receptors (V2 receptors) that are abundant in rodents but absent in man [1617].

Rhodopsin family (class A), which includes receptors for a wide variety of small molecules, neurotransmitters, peptides and hormones, together with olfactory receptors, visual pigments, taste type 2 receptors and five pheromone receptors (V1 receptors).

Adhesion family GPCRs are phylogenetically related to class B receptors, from which they differ by possessing large extracellular N-termini that are autoproteolytically cleaved from their 7TM domains at a conserved "GPCR proteolysis site" (GPS) which lies within a much larger (˜320 residue) "GPCR autoproteolysis-inducing" (GAIN) domain, an evolutionarily ancient motif also found in polycystic kidney disease 1 (PKD1)-like proteins, which has been suggested to be both required and sufficient for autoproteolysis [1909].

Frizzled family consists of 10 Frizzled proteins (FZD(1-10)) and Smoothened (SMO). The FZDs are activated by secreted lipoglycoproteins of the WNT family, whereas SMO is indirectly activated by the Hedgehog (HH) family of proteins acting on the transmembrane protein Patched (PTCH).

Secretin family, encoded by 15 genes in humans. The ligands for receptors in this family are polypeptide hormones of 27-141 amino acid residues; nine of the mammalian receptors respond to ligands that are structurally related to one another (glucagon, glucagon-like peptides (GLP-1, GLP-2), glucose-dependent insulinotropic polypeptide (GIP), secretin, vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP) and growth-hormone-releasing hormone (GHRH)) [870].

GPCR families

Family Class A Class B (Secretin) Class C (Glutamate) Adhesion Frizzled
Receptors with known ligands 197 15 12 0 11
Orphans 87 (54)a - 8 (1)a 26 (6)a 0
Sensory (olfaction) 390b,c - - - -
Sensory (vision) 10d opsins - - - -
Sensory (taste) 30c taste 2 - 3c taste 1 - -
Sensory (pheromone) 5c vomeronasal 1 - - - -
Total 719 15 22 33 11

aNumbers in brackets refer to orphan receptors for which an endogenous ligand has been proposed in at least one publication, see [485]; b[1784]; c[1617]; d[2329].

Much of our current understanding of the structure and function of GPCRs is the result of pioneering work on the visual pigment rhodopsin and on theβ2 adrenoceptor, the latter culminating in the award of the 2012 Nobel Prize in chemistry to Robert Lefkowitz and Brian Kobilka [1209, 1343].

Pseudogenes

Below is a curated list of pseudogenes that in humans are non-coding for receptor protein. In some cases these have a shared ancestry with genes that encode functional receptors in rats and mice.

ADGRE4P, GNRHR2, GPR79, HTR5BP, NPY6R, TAAR3P, TAAR4P, TAAR7P, TAS2R12P, TAS2R15P, TAS2R18P, TAS2R2P, TAS2R62P, TAS2R63P, TAS2R64P, TAS2R67P, TAS2R68P, TAS2R6P. A more detailed listing containg further information can be viewed here.

Olfactory receptors

Olfactory receptors are also seven-transmembrane spanning G protein-coupled receptors, responsible for the detection of odorants. These are not currently included as they are not yet associated with extensive pharmacological data but are curated in the following databases: The gene list of olfactory receptors at HGNC, and curated by HORDE and ORDB.

Further reading on G protein-coupled receptors

Kenakin T. (2018) Is the Quest for Signaling Bias Worth the Effort? Mol Pharmacol 93: 266-269 [PMID:29348268]

Michel MC et al. (2018) Biased Agonism in Drug Discovery-Is It Too Soon to Choose a Path? Mol Pharmacol 93: 259-265 [PMID:29326242]

Roth BL et al. (2017) Discovery of new GPCR ligands to illuminate new biology. Nat Chem Biol 13: 1143-1151 [PMID:29045379]

Sriram K et al. (2018) G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs? Mol Pharmacol 93: 251-258 [PMID:29298813]

Family structure

S30 Orphan and other 7TM receptors

S32 Class A Orphans

Class B Orphans

S41 Class C Orphans

S41 Opsin receptors

S42 Taste 1 receptors

S43 Taste 2 receptors

S44 Other 7TM proteins

S45 5-Hydroxytryptamine receptors

S48 Acetylcholine receptors (muscarinic)

S50 Adenosine receptors

S52 Adhesion Class GPCRs

S55 Adrenoceptors

S59 Angiotensin receptors

S60 Apelin receptor

S61 Bile acid receptor

S62 Bombesin receptors

S63 Bradykinin receptors

S64 Calcitonin receptors

S66 Calcium-sensing receptor

S67 Cannabinoid receptors

S68 Chemerin receptors

S69 Chemokine receptors

S73 Cholecystokinin receptors

S74 Class Frizzled GPCRs

S76 Complement peptide receptors

S78 Corticotropin-releasing factor receptors

S79 Dopamine receptors

S81 Endothelin receptors

S82 G protein-coupled estrogen receptor

S83 Formylpeptide receptors

S84 Free fatty acid receptors

S86 GABAB receptors

S87 Galanin receptors

S89 Ghrelin receptor

S90 Glucagon receptor family

S91 Glycoprotein hormone receptors

S92 Gonadotrophin-releasing hormone receptors

S93 GPR18, GPR55 and GPR119

S94 Histamine receptors

S96 Hydroxycarboxylic acid receptors

S97 Kisspeptin receptor

S98 Leukotriene receptors

S100 Lysophospholipid (LPA) receptors

S101 Lysophospholipid (S1P) receptors

S103 Melanin-concentrating hormone receptors

S104 Melanocortin receptors

S105 Melatonin receptors

S106 Metabotropic glutamate receptors

S108 Motilin receptor

S110 Neuromedin U receptors

S111 Neuropeptide FF/neuropeptide AF receptors

S112 Neuropeptide S receptor

S113 Neuropeptide W/neuropeptide B receptors

S114 Neuropeptide Y receptors

S116 Neurotensin receptors

S117 Opioid receptors

S119 Orexin receptors

S120 Oxoglutarate receptor

S120 P2Y receptors

S123 Parathyroid hormone receptors

S124 Platelet-activating factor receptor

S125 Prokineticin receptors

S126 Prolactin-releasing peptide receptor

S127 Prostanoid receptors

S129 Proteinase-activated receptors

S131 QRFP receptor

S132 Relaxin family peptide receptors

S134 Somatostatin receptors

S135 Succinate receptor

S136 Tachykinin receptors

S137 Thyrotropin-releasing hormone receptors

S138 Trace amine receptor

S139 Urotensin receptor

S140 Vasopressin and oxytocin receptors

S142 VIP and PACAP receptors

Orphan and other 7TM receptors

Overview

This set contains ’orphan’ G protein coupled receptors where the endogenous ligand(s) is not known, and other 7TM receptors.

Further reading on Orphan and other 7TM receptors

Davenport AP et al. (2013) International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol Rev 65: 967-86 [PMID:23686350]

Gilissen J et al. (2016) Insight into SUCNR1 (GPR91) structure and function. Pharmacol Ther 159: 56-65 [PMID:26808164]

Insel PA et al. (2015) G Protein-Coupled Receptor (GPCR) Expression in Native Cells: "Novel" endoGPCRs as Physiologic Regulators and Therapeutic Targets. Mol Pharmacol 88: 181-7 [PMID:25737495]

Khan MZ et al. (2017) Neuro-psychopharmacological perspective of Orphan receptors of Rhodopsin(class A) family of G protein-coupled receptors. Psychopharmacology (Berl.) 234: 1181-1207 [PMID:28289782]

Mackenzie AE et al. (2017) The emerging pharmacology and function of GPR35 in the nervous system. Neuropharmacology 113: 661-671 [PMID:26232640]

Ngo T et al. (2016) Identifying ligands at orphan GPCRs: current status using structure-based approaches. Br J Pharmacol 173: 2934-51 [PMID:26837045]

Class A Orphans

Overview

Table 1 lists a number of putative GPCRs identified by NC-IUPHAR [652], for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. These GPCRs have recently been reviewed in detail [485]. The GPCRs in Table 1 are all Class A, rhodopsin-like GPCRs. Class A orphan GPCRs not listed in Table 1 are putative GPCRs with as-yet unidentified endogenous ligands.

Table 1: Class A orphan GPCRs with putative endogenous ligands

GPR3 GPR4 GPR6 GPR12 GPR15 GPR17 GPR20
GPR22 GPR26 GPR31 GPR34 GPR35 GPR37 GPR39
GPR50 GPR63 GRP65 GPR68 GPR75 GPR84 GPR87
GPR88 GPR132 GPR149 GPR161 GPR183 LGR4 LGR5
LGR6 MAS1 MRGPRD MRGPRX1 MRGPRX2 P2RY10 TAAR2

In addition the orphan receptors GPR18, GPR55 and GPR119 which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (GPR18, GPR55 and GPR119).

Further reading on Class A Orphans

McNeil BD et al. (2015) Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature 519: 237-41 [PMID:25517090]

Wirthgen E et al. (2017) Kynurenic Acid: The Janus-Faced Role of an Immunomodulatory Tryptophan Metabolite and Its Link to Pathological Conditions. Front Immunol 8: 1957 [PMID:29379504]

Nomenclature GPR3 GPR4
HGNC, UniProt GPR3, P46089 GPR4, P46093
Endogenous ligands Protons
Agonists diphenyleneiodonium chloride [2626]
Comments Sphingosine 1-phosphate was reported to be an endogenous agonist [2392], but this finding was not replicated in subsequent studies [2630]. Reported to activate adenylyl cyclase constitutively through Gs [584]. Gene disruption results in premature ovarian ageing [1332], reduced β-amyloid deposition [2333] and hypersensitivity to thermal pain [2026] in mice. First small molecule inverse agonist [1067] and agonists identified [2626]. An initial report suggesting activation by lysophosphatidylcholine and sphingosylphosphorylcholine [2688] has been retracted [1746]. GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [485, 2129]. Gene disruption is associated with increased perinatal mortality and impaired vascular proliferation [2616]. Negative allosteric modulators of GPR4 have been reported [2358].

Nomenclature GPR6 GPR12 GPR15
HGNC, UniProt GPR6, P46095 GPR12, P47775 GPR15, P49685
Comments An initial report that sphingosine 1-phosphate (S1P) was a high-affinity ligand (EC50 value of 39nM) [1012, 2392] was not repeated in arrestin-based assays [2218, 2630]. Reported to activate adenylyl cyclase constitutively through Gs and to be located intracellularly [1801]. GPR6-deficient mice showed reduced striatal cyclic AMP production in vitro and selected alterations in instrumental conditioning in vivo. [1425]. Reports that sphingosine 1-phosphate is a ligand of GPR12 [1011, 2392] have not been replicated in arrestin-based assays [2218, 2630]. Gene disruption results in dyslipidemia and obesity [183]. Reported to act as a co-receptor for HIV [580]. In an infection-induced colitis model, Gpr15 knockout mice were more prone to tissue damage and inflammatory cytokine expression [1174].

Nomenclature GPR17 GPR19 GPR20 GPR21
HGNC, UniProt GPR17, Q13304 GPR19, Q15760 GPR20, Q99678 GPR21, Q99679
Endogenous agonists UDP-glucose [155, 419], LTC4 [419], UDP-galactose [155, 419], uridine diphosphate [155, 419], LTD4 [419]
Agonists adropin (ENHO, Q6UWT2) [1946]
Comments Reported to be a dual leukotriene and uridine diphosphate receptor [419]. Another group instead proposed that GPR17 functions as a negative regulator of the CysLT1 receptor response to leukotriene D4 (LTD4). For further discussion, see [485]. Reported to antagonize CysLT1 receptor signalling in vivo and in vitro [1473]. See reviews [100] and [485]. Reported to inhibit adenylyl cyclase constitutively through Gi/o [876]. GPR20 deficient mice exhibit hyperactivity characterised by increased total distance travelled in an open field test [247]. Gpr21 knockout mice were resistant to diet-induced obesity, exhibiting an increase in glucose tolerance and insulin sensitivity, as well as a modest lean phenotype [1793].

Nomenclature GPR22 GPR25 GPR26 GPR27 GPR31 GPR32 GPR33
HGNC, UniProt GPR22, Q99680 GPR25, O00155 GPR26, Q8NDV2 GPR27, Q9NS67 GPR31, O00270 GPR32, O75388 GPR33, Q49SQ1
Potency order of endogenous ligands resolvin D1> LXA4
Endogenous agonists 12S-HETE [825] – Mouse resolvin D1 [1248], LXA4 [1248]
Labelled ligands [3H]resolvin D1 (Agonist) [1248]
Comments Gene disruption results in increased severity of functional decompensation following aortic banding [13]. Identified as a susceptibility locus for osteoarthritis [613, 1153, 2410]. Has been reported to activate adenylyl cyclase constitutively through Gs [1091]. Gpr26 knockout mice show increased levels of anxiety and depression-like behaviours [2663]. Knockdown of Gpr27 reduces endogenous mouse insulin promotor activity and glucose-stimulated insulin secretion [1255]. See [485] for discussion of pairing. Resolvin D1 has been demonstrated to activate GPR32 in two publications [386, 1248]. The pairing was not replicated in a recent study based on arrestin recruitment [2218]. GPR32 is a pseudogene in mice and rats. See reviews [100] and [485]. GPR33 is a pseudogene in most individuals, containing a premature stop codon within the coding sequence of the second intracellular loop [2004].

Nomenclature GPR34 GPR35
HGNC, UniProt GPR34, Q9UPC5 GPR35, Q9HC97
Endogenous agonists lysophosphatidylserine [1193, 2261] 2-oleoyl-LPA [1776], kynurenic acid [2218, 2483]
Comments Lysophosphatidylserine has been reported to be a ligand of GPR34 in several publications, but the pairing was not replicated in a recent study based on arrestin recruitment [2218]. Fails to respond to a variety of lipid-derived agents [2630]. Gene disruption results in an enhanced immune response [1387]. Characterization of agonists at this receptor is discussed in [1017] and [485]. Several studies have shown that kynurenic acid is an agonist of GPR35 but it remains controversial whether the proposed endogenous ligand reaches sufficient tissue concentrations to activate the receptor [1256]. 2-oleoyl-LPA has also been proposed as an endogenous ligand [1776] but these results were not replicated in an arrestin assay [2218]. The phosphodiesterase inhibitor zaprinast [2323] has become widely used as a surrogate agonist to investigate GPR35 pharmacology and signalling [2323]. GPR35 is also activated by the pharmaceutical adjunct pamoic acid [2677]. See reviews [485] and [539].

Nomenclature GPR37 GPR37L1 GPR39
HGNC, UniProt GPR37, O15354 GPR37L1, O60883 GPR39, O43194
Endogenous agonists Zn2+ [963]
Agonists neuropeptide head activator [1976]
Comments Reported to associate and regulate the dopamine transporter [1506] and to be a substrate for parkin [1504]. Gene disruption results in altered striatal signalling [1505]. The peptides prosaptide and prosaposin are proposed as endogenous ligands for GPR37 and GPR37L1 [1568]. The peptides prosaptide and prosaposin are proposed as endogenous ligands for GPR37 and GPR37L1 [1568]. Zn2+ has been reported to be a potent and efficacious agonist of human, mouse and rat GPR39 [2623]. Obestatin (GHRL, Q9UBU3), a fragment from the ghrelin precursor, was reported initially as an endogenous ligand, but subsequent studies failed to reproduce these findings. GPR39 has been reported to be down-regulated in adipose tissue in obesity-related diabetes [326]. Gene disruption results in obesity and altered adipocyte metabolism [1860]. Reviewed in [485].

Nomenclature GPR45 GPR50 GPR52 GPR61 GPR62 GPR63
HGNC, UniProt GPR45, Q9Y5Y3 GPR50, Q13585 GPR52, Q9Y2T5 GPR61, Q9BZJ8 GPR62, Q9BZJ7 GPR63, Q9BZJ6
Comments GPR50 is structurally related to MT1 and MT2 melatonin receptors, with which it heterodimerises constitutively and specifically [1366]. Gpr50 knockout mice display abnormal thermoregulation and are much more likely than wild-type mice to enter fasting-induced torpor [137]. First small molecule agonist reported [2128]. GPR61 deficient mice exhibit obesity associated with hyperphagia [1692]. Although no endogenous ligands have been identified, 5-(nonyloxy)tryptamine has been reported to be a low affinity inverse agonist [2307]. Sphingosine 1-phosphate and dioleoylphosphatidic acid have been reported to be low affinity agonists for GPR63 [1731] but this finding was not replicated in an arrestin-based assay [2630].

Nomenclature GPR65 GPR68 GPR75 GPR78 GPR79
HGNC, UniProt GPR65, Q8IYL9 GPR68, Q15743 GPR75, O95800 GPR78, Q96P69 GPR79, –
Endogenous ligands Protons Protons
Allosteric modulators ogerin (Positive) (pKB 5) [995], lorazepam (Positive) [995]
Comments GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [485, 2129]. Reported to activate adenylyl cyclase; gene disruption leads to reduced eosinophilia in models of allergic airway disease [1237]. GPR68 was previously identified as a receptor for sphingosylphosphorylcholine (SPC) [2594], but the original publication has been retracted [1]. GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [485, 2129]. A family of 3,5-disubstituted isoxazoles were identified as agonists of GPR68 [2028]. CCL5 (CCL5, P13501) was reported to be an agonist of GPR75 [1013], but the pairing could not be repeated in an arrestin assay [2218]. GPR78 has been reported to be constitutively active, coupled to elevated cAMP production [1091].

Nomenclature GPR82 GPR83 GPR84 GPR85 GPR87
HGNC, UniProt GPR82, Q96P67 GPR83, Q9NYM4 GPR84, Q9NQS5 GPR85, P60893 GPR87, Q9BY21
Endogenous agonists LPA [1673, 2287]
Agonists PEN {Mouse} [771] – Mouse, Zn2+ [1664] – Mouse decanoic acid [2218, 2484], undecanoic acid [2484], lauric acid [2484], 6-nonylpyridine-2,4-diol (orthosteric) [1512], DL-175 (orthosteric) [1512], Embelin (orthosteric) [1512], PSB-16434 (orthosteric) [1512], ZQ-16 (orthosteric) [1512]
Allosteric modulators DIM (Agonist) [1512]
Comments Mice with Gpr82 knockout have a lower body weight and body fat content associated with reduced food intake, decreased serum triglyceride levels, as well as higher insulin sensitivity and glucose tolerance [597]. One isoform has been implicated in the induction of CD4(+) CD25(+) regulatory T cells (Tregs) during inflammatory immune responses [861]. The extracellular N-terminal domain is reported as an intramolecular inverse agonist [1665]. Medium chain free fatty acids with carbon chain lengths of 9-14 activate GPR84 [2275, 2484]. A surrogate ligand for GPR84, 6-n-octylaminouracil has also been proposed [2275]. See review [485] for discussion of classification. Mutational analysis and molecular modelling of GPR84 has been reported [1735]. Proposed to regulate hippocampal neurogenesis in the adult, as well as neurogenesis-dependent learning and memory [368].

Nomenclature GPR88 GPR101 GPR132 GPR135 GPR139 GPR141 GPR142
HGNC, UniProt GPR88, Q9GZN0 GPR101, Q96P66 GPR132, Q9UNW8 GPR135, Q8IZ08 GPR139, Q6DWJ6 GPR141, Q7Z602 GPR142, Q7Z601
Endogenous ligands Protons
Comments Gene disruption results in altered striatal signalling [1428]. Small molecule agonists have been reported [176]. Mutations in GPR101 have been linked to gigantism and acromegaly [2377]. GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [485, 2129]. Reported to respond to lysophosphatidylcholine [1102], but later retracted [2556]. Peptide agonists have been reported [1026]. Small molecule agonists have been reported [2359, 2647].

Nomenclature GPR146 GPR148 GPR149 GPR150 GPR151 GPR152 GPR153
HGNC, UniProt GPR146, Q96CH1 GPR148, Q8TDV2 GPR149, Q86SP6 GPR150, Q8NGU9 GPR151, Q8TDV0 GPR152, Q8TDT2 GPR153, Q6NV75
Comments Yosten et al. demonstrated inhibition of proinsulin C-peptide (INS, P01308)-induced stimulation of cFos expression folllowing knockdown of GPR146 in KATO III cells, suggesting proinsulin C-peptide as an endogenous ligand of the receptor [2644]. Reviewed in [1403]. Gpr149 knockout mice displayed increased fertility and enhanced ovulation, with increased levels of FSH receptor and cyclin D2 mRNA levels [581]. GPR151 responded to galanin with an EC50 value of 2 µM, suggesting that the endogenous ligand shares structural features with galanin (GAL, P22466) [1010].

Nomenclature GPR160 GPR161 GPR162 GPR171 GPR173 GPR174
HGNC, UniProt GPR160, Q9UJ42 GPR161, Q8N6U8 GPR162, Q16538 GPR171, O14626 GPR173, Q9NS66 GPR174, Q9BXC1
Endogenous agonists lysophosphatidylserine [1021]
Comments A C-terminal truncation (deletion) mutation in Gpr161 causes congenital cataracts and neural tube defects in the vacuolated lens (vl) mouse mutant [1532]. The mutated receptor is associated with cataract, spina bifida and white belly spot phenotypes in mice [1232]. Gene disruption is associated with a failure of asymmetric embryonic development in zebrafish [1362]. GPR171 has been shown to be activated by the endogenous peptide BigLEN {Mouse}. This receptor-peptide interaction is believed to be involved in regulating feeding and metabolism responses [770]. See [1017] which discusses characterization of agonists at this receptor.

Nomenclature GPR176 GPR182 GPR183
HGNC, UniProt GPR176, Q14439 GPR182, O15218 GPR183, P32249
Endogenous agonists 7α,25-dihydroxycholesterol [857, 1415], 7α,27-dihydroxycholesterol [1415], 7β, 25-dihydroxycholesterol [1415], 7β, 27-dihydroxycholesterol [1415]
Comments Rat GPR182 was first proposed as the adrenomedullin receptor [1119]. However, it was later reported that rat and human GPR182 did not respond to adrenomedullin [1149] and GPR182 is not currently considered to be a genuine adrenomedullin receptor [894]. Two independent publications have shown that 7α,25-dihydroxycholesterol is an agonist of GPR183 and have demonstrated by mass spectrometry that this oxysterol is present endogenously in tissues [857, 1415]. Gpr183-deficient mice show a reduction in the early antibody response to a T-dependent antigen. GPR183-deficient B cells fail to migrate to the outer follicle and instead stay in the follicle centre [1141, 1848].

Nomenclature LGR4 LGR5 LGR6
HGNC, UniProt LGR4, Q9BXB1 LGR5, O75473 LGR6, Q9HBX8
Endogenous agonists R-spondin-2 (RSPO2, Q6UXX9) [315], R-spondin-1 (RSPO1, Q2MKA7) [315], R-spondin-3 (RSPO3, Q9BXY4) [315], R-spondin-4 (RSPO4, Q2I0M5) [315] R-spondin-2 (RSPO2, Q6UXX9) [315], R-spondin-1 (RSPO1, Q2MKA7) [315], R-spondin-3 (RSPO3, Q9BXY4) [315], R-spondin-4 (RSPO4, Q2I0M5) [315] R-spondin-1 (RSPO1, Q2MKA7) [315, 499], R-spondin-2 (RSPO2, Q6UXX9) [315, 499], R-spondin-3 (RSPO3, Q9BXY4) [315, 499], R-spondin-4 (RSPO4, Q2I0M5) [315, 499]
Comments LGR4 does not couple to heterotrimeric G proteins or recruit arrestins when stimulated by the R-spondins, indicating a unique mechanism of action. R-spondins bind to LGR4, which specifically associates with Frizzled and LDL receptor-related proteins (LRPs) that are activated by the extracellular Wnt molecules and then trigger canonical Wnt signalling to increase gene expression [315, 499, 2022]. Gene disruption leads to multiple developmental disorders [1077, 1447, 2214, 2518]. The four R-spondins can bind to LGR4, LGR5, and LGR6, which specifically associate with Frizzled and LDL receptor-related proteins (LRPs), proteins that are activated by extracellular Wnt molecules and which then trigger canonical Wnt signalling to increase gene expression [315, 499].

Nomenclature MAS1 MAS1L MRGPRD MRGPRE MRGPRF
HGNC, UniProt MAS1, P04201 MAS1L, P35410 MRGPRD, Q8TDS7 MRGPRE, Q86SM8 MRGPRF, Q96AM1
Endogenous agonists β-alanine [2158, 2218]
Agonists angiotensin-(1-7) (AGT, P01019) [758] – Mouse
Comments An endogenous peptide with a high degree of sequence similarity to angiotensin-(1-7) (AGT, P01019), alamandine (AGT), was shown to promote NO release in MRGPRD-transfected cells. The binding of alamandine to MRGPRD to was shown to be blocked by D-Pro7-angiotensin-(1-7), β-alanine and PD123319 [1303]. Genetic ablation of MRGPRD+ neurons of adult mice decreased behavioural sensitivity to mechanical stimuli but not to thermal stimuli [334]. See reviews [485] and [2212]. See reviews [485] and [2212]. MRGPRF has been reported to respond to stimulation by angiotensin metabolites [726]. See reviews [485] and [2212].

Nomenclature MRGPRG MRGPRX1 MRGPRX2 MRGPRX3 MRGPRX4 P2RY8 P2RY10
HGNC, UniProt MRGPRG, Q86SM5 MRGPRX1, Q96LB2 MRGPRX2, Q96LB1 MRGPRX3, Q96LB0 MRGPRX4, Q96LA9 P2RY8, Q86VZ1 P2RY10, O00398
Endogenous agonists bovine adrenal medulla peptide 8-22 (PENK, P01210) [363, 1353, 2218] PAMP-20 (ADM, P35318) [1112] sphingosine 1-phosphate [1673], LPA [1673]
Agonists cortistatin-14 {Mouse, Rat} [1112, 1296, 1998, 2218]
Selective agonists PAMP-12 (human) [1112]
Comments See reviews [485] and [2212]. Reported to mediate the sensation of itch [1419, 2169]. Reports that bovine adrenal medulla peptide 8-22 (PENK, P01210) was the most potent of a series of proenkephalin A-derived peptides as an agonist of MRGPRX1 in assays of calcium mobilisation and radioligand binding [1353] were replicated in an independent study using an arrestin recruitment assay [2218]. See reviews [485] and [2212]. A diverse range of substances has been reported to be agonists of MRGPRX2, with cortistatin 14 the highest potency agonist in assays of calcium mobilisation [1998], also confirmed in an independent study using an arrestin recruitment assay [2218]. See reviews [485] and [2212]. See reviews [485] and [2212].

Nomenclature TAAR2 TAAR3 TAAR4P TAAR5 TAAR6 TAAR8 TAAR9
HGNC, UniProt TAAR2, Q9P1P5 TAAR3P, Q9P1P4 TAAR4P, – TAAR5, O14804 TAAR6, Q96RI8 TAAR8, Q969N4 TAAR9, Q96RI9
Potency order of endogenous ligands β-phenylethylamine> tryptamine [219]
Comments Probable pseudogene in 10-15% of Asians due to a polymorphism (rs8192646) producing a premature stop codon at amino acid 168 [485]. TAAR3 is thought to be a pseudogene in man though functional in rodents [485]. Pseudogene in man but functional in rodents [485]. Trimethylamine is reported as an agonist [2471] and 3-iodothyronamine an inverse agonist [536]. TAAR9 appears to be functional in most individuals but has a polymorphic premature stop codon at amino acid 61 (rs2842899) with an allele frequency of 10-30% in different populations [2428].

Class C Orphans

Overview

This set contains class C ’orphan’ G protein coupled receptors where the endogenous ligand(s) is not known.

Further reading on Class C Orphans

Harpsøe K et al. (2017) Structural insight to mutation effects uncover a common allosteric site in class C GPCRs. Bioinformatics 33: 1116-1120 [PMID:28011766]

Nomenclature GPR156 GPR158 GPR179 GPRC5A GPRC5B GPRC5C GPRC5D GPRC6 receptor
HGNC, UniProt GPR156, Q8NFN8 GPR158, Q5T848 GPR179, Q6PRD1 GPRC5A, Q8NFJ5 GPRC5B, Q9NZH0 GPRC5C, Q9NQ84 GPRC5D, Q9NZD1 GPRC6A, Q5T6X5
Comments GPRC6 is a Gq-coupled receptor which responds to basic amino acids [2515].

Opsin receptors

Nomenclature OPN3 OPN4 OPN5
HGNC, UniProt OPN3, Q9H1Y3 OPN4, Q9UHM6 OPN5, Q6U736
Comments Evidence indicates that UV light triggers OPN5 to activate Gi-mediated signalling in mammalian tissues [1219].

Taste 1 receptors

Overview

Whilst the taste of acid and salty foods appear to be sensed by regulation of ion channel activity, bitter, sweet and umami tastes are sensed by specialised GPCR. Two classes of taste GPCR have been identified, T1R and T2R, which are similar in sequence and structure to Class C and Class A GPCR, respectively. Activation of taste receptors appears to involve gustducin-(Gαt3) and Gα14-mediated signalling, although the precise mechanisms remain obscure. Gene disruption studies suggest the involvement of PLCβ2 [2673], TRPM5 [2673] and IP3 [948] receptors in post-receptor signalling of taste receptors. Although predominantly associated with the oral cavity, taste receptors are also located elsewhere, including further down the gastrointestinal system, in the lungs and in the brain.

Sweet/Umami: T1R3 acts as an obligate partner in T1R1/T1R3 and T1R2/T1R3 heterodimers, which sense umami or sweet, respectively. T1R1/T1R3 heterodimers respond to L-glutamic acid and may be positively allosterically modulated by 5’-nucleoside monophosphates, such as 5’-GMP [1377]. T1R2/T1R3 heterodimers respond to sugars, such as sucrose, and artificial sweeteners, such as saccharin [1711].

Further reading on Taste 1 receptors

Behrens M and Ziegler F (2020) Structure-Function Analyses of Human Bitter Taste Receptors-Where Do We Stand? Molecules 25: [PMID:32993119]

Palmer RK. (2019) A Pharmacological Perspective on the Study of Taste. Pharmacol Rev 71: 20-48 [PMID:30559245]

Nomenclature TAS1R1 TAS1R2 TAS1R3
HGNC, UniProt TAS1R1, Q7RTX1 TAS1R2, Q8TE23 TAS1R3, Q7RTX0

Comments

Positive allosteric modulators of T1R2/T1R3 have been reported [2597]. Such compounds enhance the sweet taste of sucrose mediated by these receptors, but are tasteless on their own.

Taste 2 receptors

Overview

The composition and stoichiometry of bitter taste receptors is not yet established. Bitter receptors appear to separate into two groups, with very restricted ligand specificity or much broader responsiveness. For example, T2R5 responded to cycloheximide, but not 10 other bitter compounds [347], while T2R14 responded to at least eight different bitter tastants, including (-)-α-thujone and picrotoxinin [145].

Specialist database BitterDB contains additional information on bitter compounds and receptors [2541].

Further reading on Taste 2 receptors

Palmer RK. (2019) A Pharmacological Perspective on the Study of Taste. Pharmacol Rev 71: 20-48 [PMID:30559245]

Nomenclature TAS2R1 TAS2R3 TAS2R4 TAS2R5 TAS2R7 TAS2R8 TAS2R9
HGNC, UniProt TAS2R1, Q9NYW7 TAS2R3, Q9NYW6 TAS2R4, Q9NYW5 TAS2R5, Q9NYW4 TAS2R7, Q9NYW3 TAS2R8, Q9NYW2 TAS2R9, Q9NYW1
Agonists T5-8 [1166]

Nomenclature TAS2R10 TAS2R13 TAS2R14 TAS2R16 TAS2R19 TAS2R20 TAS2R30
HGNC, UniProt TAS2R10, Q9NYW0 TAS2R13, Q9NYV9 TAS2R14, Q9NYV8 TAS2R16, Q9NYV7 TAS2R19, P59542 TAS2R20, P59543 TAS2R30, P59541

Nomenclature TAS2R31 TAS2R38 TAS2R39 TAS2R40
HGNC, UniProt TAS2R31, P59538 TAS2R38, P59533 TAS2R39, P59534 TAS2R40, P59535
Antagonists 6-methoxysakuranetin (pIC50 5.6) [1184], GIV3727 (pIC50 5.1–5.2) [2185]
Comments Individuals who are homozygous for the PAV variant of TAS2R38 (so-called ’super-tasters’) are hyper-sensitive to the bitter tastes of certain chemicals that are present in some green vegetables (broccoli, sprouts), beer, coffee and dark chocolate. This makes eating these foods exceptionally unpleasant for carriers of this genetic variant.

Nomenclature TAS2R41 TAS2R42 TAS2R43 TAS2R45 TAS2R46 TAS2R50 TAS2R60
HGNC, UniProt TAS2R41, P59536 TAS2R42, Q7RTR8 TAS2R43, P59537 TAS2R45, P59539 TAS2R46, P59540 TAS2R50, P59544 TAS2R60, P59551

Other 7TM proteins

These proteins are predicted to have 7TM domains, but functional studies have yet to confirm them as G protein-coupled receptors.

Nomenclature GPR107 GPR137 TPRA1 GPR143 GPR157
HGNC, UniProt GPR107, Q5VW38 GPR137, Q96N19 TPRA1, Q86W33 GPR143, P51810 GPR157, Q5UAW9
Endogenous agonists levodopa [1433]
Comments GPR107 is a member of the LUSTR family of proteins found in both plants and animals, having similar topology to G protein-coupled receptors [579] TPRA1 shows no homology to known G protein-coupled receptors. Loss-of-function mutations underlie ocular albinism type 1 [128]. GPR157 has ambiguous sequence similarities to several different GPCR families (class A, class B and the slime mould cyclic AMP receptor). Because of its distant relationship to other GPCRs, it cannot be readily classified.

5-Hydroxytryptamine receptors

Overview

5-HT receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on 5-HT receptors [982] and subsequently revised [875]) are, with the exception of the ionotropic 5-HT3 class, GPCRs where the endogenous agonist is 5-hydroxytryptamine. The diversity of metabotropic 5-HT receptors is increased by alternative splicing that produces isoforms of the 5-HT2A (non-functional), 5-HT2C (non-functional), 5-HT4, 5-HT6 (non-functional) and 5-HT7 receptors. Unique amongst the GPCRs, RNA editing produces 5-HT2C receptor isoforms that differ in function, such as efficiency and specificity of coupling to Gq/11 and also pharmacology [195, 2525]. Most 5-HT receptors (except 5-ht1e and 5-ht5b) play specific roles mediating functional responses in different tissues (reviewed by [1940, 2445]).

Further reading on 5-Hydroxytryptamine receptors

Bockaert J et al. (2011) 5-HT(4) receptors, a place in the sun: act two. Curr Opin Pharmacol 11: 87-93 [PMID:21342787]

Hayes DJ et al. (2011) 5-HT receptors and reward-related behaviour: a review. Neurosci Biobehav Rev 35: 1419-49 [PMID:21402098]

Hoyer D et al. (1994) International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev 46: 157-203 [PMID:7938165]

Leopoldo M et al. (2011) Serotonin 5-HT7 receptor agents: Structure-activity relationships and potential therapeutic applications in central nervous system disorders. Pharmacol Ther 129: 120-48 [PMID:20923682]

Meltzer HY et al. (2011) The role of serotonin receptors in the action of atypical antipsychotic drugs. Curr Opin Pharmacol 11: 59-67 [PMID:21420906]

Roberts AJ et al. (2012) The 5-HT(7) receptor in learning and memory. Hippocampus 22: 762-71 [PMID:21484935]

Nomenclature 5-HT1A receptor 5-HT1B receptor 5-HT1D receptor 5-ht1e receptor 5-HT1F receptor
HGNC, UniProt HTR1A, P08908 HTR1B, P28222 HTR1D, P28221 HTR1E, P28566 HTR1F, P30939
Agonists U92016A [1545], vilazodone (Partial agonist) [494], vortioxetine (Partial agonist) [114] L-694,247 [791], naratriptan (Partial agonist) [1695], eletriptan [1695], frovatriptan [2595], zolmitriptan (Partial agonist) [1695], vortioxetine (Partial agonist) [114], rizatriptan (Partial agonist) [1695] dihydroergotamine [847, 1361, 1368], ergotamine [762], L-694,247 [2577], naratriptan [544, 1695, 1975], zolmitriptan [1695], frovatriptan [2595], rizatriptan [1695] BRL-54443 [267] BRL-54443 [267], eletriptan [1695], sumatriptan [15, 16, 1695, 2464]
Selective agonists 8-OH-DPAT [505, 848, 1109, 1351, 1585, 1722, 1724, 1725], NLX-101 [1723] CP94253 [1210] PNU109291 [603] – Gorilla, eletriptan [1695] lasmiditan [1710], LY334370 [2464], 5-BODMT [1200], LY344864 [1867]
Antagonists (S)-UH 301 (pKi 7.9) [1722]
Selective antagonists WAY-100635 (pKi 7.9–9.2) [1722, 1724], robalzotan (pKi 9.2) [1082] SB 224289 (Inverse agonist) (pKi 8.2–8.6) [717, 1720, 2121], SB236057 (Inverse agonist) (pKi 8.2) [1578], GR-55562 (pKB 7.4) [983] SB 714786 (pKi 9.1) [2495]
Labelled ligands [3H]robalzotan (Antagonist) (pKd 9.8) [1069], [3H]WAY100635 (Antagonist) (pKd 9.5) [1156], [3H]8-OH-DPAT (Agonist) [188, 1109, 1721, 1724], [3H]NLX-112 (Agonist) [928], [11C]WAY100635 (Antagonist) [2384], p-[18F]MPPF (Antagonist) [445] [3H]N-methyl-AZ10419369 (Agonist, Partial agonist) [1478], [3H]GR 125,743 (Selective Antagonist) (pKd 8.6–9.2) [791, 2587], [3H]alniditan (Agonist) [1361], [125I]GTI (Agonist) [228, 273] – Rat, [3H]eletriptan (Agonist, Partial agonist) [1695], [3H]sumatriptan (Agonist, Partial agonist) [1695], [11C]AZ10419369 (Agonist, Partial agonist) [2433] [3H]eletriptan (Agonist) [1695], [3H]alniditan (Agonist) [1361], [125I]GTI (Selective Agonist) [228, 273] – Rat, [3H]GR 125,743 (Selective Antagonist) (pKd 8.6) [2587], [3H]sumatriptan (Agonist) [1695] [3H]5-HT (Agonist) [1541, 1816] [3H]LY334370 (Agonist) [2464], [125I]LSD (Agonist) [51] – Mouse

Nomenclature 5-HT2A receptor 5-HT2B receptor 5-HT2C receptor
HGNC, UniProt HTR2A, P28223 HTR2B, P41595 HTR2C, P28335
Agonists DOI [242, 1709, 2187] methysergide (Partial agonist) [1205, 2014, 2465], DOI [1274, 1709, 2076] DOI [583, 1709, 2076], Ro 60-0175 [1183, 1205]
Selective agonists BW723C86 [135, 1205, 2076], Ro 60-0175 [1205] WAY-163909 [574], lorcaserin [2346]
Antagonists risperidone (Inverse agonist) (pKi 9.3–10) [1223, 1251, 2096], mianserin (pKi 7.7–9.6) [1205, 1238, 1585], ziprasidone (pKi 8.8–9.5) [1223, 1251, 2096, 2136], volinanserin (pIC50 6.5–9.3) [1205, 1434, 1961], blonanserin (pKi 9.1) [1761], clozapine (Inverse agonist) (pKi 7.6–9) [1205, 1251, 1582, 2096, 2427], H05 (pIC50 7.2) [2593] mianserin (pKi 7.9–8.8) [214, 1205, 2465] mianserin (Inverse agonist) (pKi 8.3–9.2) [648, 1205, 1585], methysergide (pKi 8.6–9.1) [583, 1205], ziprasidone (Inverse agonist) (pKi 7.9–9) [921, 1251, 2136], olanzapine (Inverse agonist) (pKi 8.1–8.4) [921, 1251, 2136], loxapine (Inverse agonist) (pKi 7.8–8) [921, 1251]
Selective antagonists compound 3b (pKi 10.6) [644], ketanserin (pKi 8.1–9.7) [278, 1205, 1947], pimavanserin (Inverse agonist) (pKi 9.3) [706, 2427] BF-1 (pKi 10.1) [2089], RS-127445 (pKi 9–9.5) [214, 1205], EGIS-7625 (pKi 9) [1238] FR260010 (pKi 9) [865], SB 242084 (pKi 8.2–9) [1150, 1205], RS-102221 (pKi 8.3–8.4) [215, 1205]
Labelled ligands [3H]fananserin (Antagonist) (pKd 9.9) [1485] – Rat, [3H]ketanserin (Antagonist) (pKd 8.6–9.7) [1205, 1947], [11C]volinanserin (Antagonist) [841], [18F]altanserin (Antagonist) [2010] [3H]LSD (Agonist) [1947], [3H]5-HT (Agonist) [2463] – Rat, [3H]mesulergine (Antagonist, Inverse agonist) (pKd 7.9) [1205], [125I]DOI (Agonist) [3H]mesulergine (Antagonist, Inverse agonist) (pKd 8.7–9.3) [648, 1947], [125I]DOI (Agonist) [648], [3H]LSD (Agonist)

Nomenclature 5-HT4 receptor 5-HT5A receptor 5-ht5b receptor
HGNC, UniProt HTR4, Q13639 HTR5A, P47898 HTR5BP, –
Agonists cisapride (Partial agonist) [96, 153, 738, 1571, 1572, 2415]
Selective agonists TD-8954 [1554], ML 10302 (Partial agonist) [165, 192, 1571, 1572, 1573], RS67506 [905] – Rat, relenopride (Partial agonist) [751], velusetrag [1430, 2197], BIMU 8 [423]
Selective antagonists RS 100235 (pKi 8.7–12.2) [423, 1992], SB 204070 (pKi 9.8–10.4) [153, 1571, 1572, 2415], GR 113808 (pKi 9.3–10.3) [96, 153, 192, 423, 1572, 1992, 2415] SB 699551 (pKi 8.2) [443]
Labelled ligands [3H]GR 113808 (Antagonist) (pKd 9.7–10.3) [96, 153, 1573, 2415], [123I]SB 207710 (Antagonist) (pKd 10.1) [268] – Pig, [3H]RS 57639 (Selective Antagonist) (pKd 9.7) [213] – Guinea pig, [11C]SB207145 (Antagonist) (pKd 8.6) [1465] [125I]LSD (Agonist) [790], [3H]5-CT (Agonist) [790] [125I]LSD (Agonist) [1533] – Mouse, [3H]5-CT (Agonist) [2462] – Mouse

Nomenclature 5-HT6 receptor 5-HT7 receptor
HGNC, UniProt HTR6, P50406 HTR7, P34969
Selective agonists WAY-181187 [2080], E6801 (Partial agonist) [958], WAY-208466 [164], EMD-386088 [1534] LP-12 [1357], LP-44 [1357], LP-211 [1358] – Rat, AS-19 [1176], E55888 [245]
Antagonists lurasidone (pKi 9.3) [1027], pimozide (pKi 9.3) [2013] – Rat, vortioxetine (pKi 6.3) [114]
Selective antagonists SB399885 (pKi 9) [947], SB 271046 (pKi 8.9) [264], cerlapirdine (pKi 8.9) [433], SB357134 (pKi 8.5) [265], Ro 63-0563 (pKi 7.9–8.4) [198, 2186] SB269970 (pKi 8.6–8.9) [2340], SB656104 (pKi 8.7) [653], DR-4004 (pKi 8.7) [761, 1163], JNJ-18038683 (pKi 8.2) [211], SB 258719 (Inverse agonist) (pKi 7.5) [2341]
Labelled ligands [11C]GSK215083 (Antagonist) (pKi 9.8) [1815], [125I]SB258585 (Selective Antagonist) (pKd 9) [947], [3H]LSD (Agonist) [197], [3H]Ro 63-0563 (Antagonist) (pKd 8.3) [198], [3H]5-CT (Agonist) [3H]5-CT (Agonist) [2340], [3H]5-HT (Agonist) [117, 2231], [3H]SB269970 (Selective Antagonist) (pKd 8.9) [2340], [3H]LSD (Agonist) [2231]

Comments

Tabulated pKi and KD values refer to binding to human 5-HT receptors unless indicated otherwise. The nomenclature of 5-HT1B/5-HT1D receptors has been revised [875]. Only the non-rodent form of the receptor was previously called 5-HT1D: the human 5-HT1B receptor (tabulated) displays a different pharmacology to the rodent forms of the receptor due to Thr335 of the human sequence being replaced by Asn in rodent receptors [858]. Wang et al. (2013) report X-ray structures which reveal the binding modality of ergotamine and dihydroergotamine (DHE) to the 5-HT1B receptor in comparison with the structure of the 5-HT2B receptor [2479]; some of these drugs adopt rather different conformations depending on the target receptor [1843]. Various 5-HT receptors have multiple partners in addition to G proteins, which may affect function and pharmacology [1509]. NAS181 is a selective antagonist of the rodent 5-HT1B receptor. Fananserin (LSD) and ketanserin bind with high affinity to dopamine D4 and histamine H1 receptors respectively, and ketanserin is a potentα1 adrenoceptor antagonist, in addition to blocking 5-HT2A receptors. Lysergic acid(LSD) and ergotamine show a strong preference for arrestin recruitment over G protein coupling at the 5-HT2B receptor, with no such preference evident at 5-HT1B receptors, and they also antagonise 5-HT7A receptors [2460]. DHE (dihydroergocryptine), pergolide and cabergoline also show significant preference for arrestin recruitment over G protein coupling at 5-HT2B receptors [2460]. The 5-HT2B (and other 5-HT) receptors interact with immunocompetent cells [1802]. The serotonin antagonist mesulergine was key to the discovery of the 5-HT2C receptor [1833], initially known as 5-HT1C [90]. The human 5-HT5A receptor may couple to several signal transduction pathways when stably expressed in C6 glioma cells [1748] and rodent prefrontal cortex (layer V pyramidal neurons) [777]. The human orthologue of the mouse 5-ht5b receptor is non-functional(stop codons); the 5-ht1e receptor has not been cloned from mouse, or rat, impeding definition of its function [858]. In addition to accepted receptors, an ’orphan’ receptor, unofficially termed 5-HT1P, has been described [743].

Acetylcholine receptors (muscarinic)

Overview

Muscarinic acetylcholine receptors (mAChRs) (nomenclature as agreed by the NC-IUPHAR Subcommittee on Muscarinic Acetylcholine Receptors [330]) are activated by the endogenous agonist acetylcholine. All five(M1-M5) mAChRs are ubiquitously expressed in the human body and are therefore attractive targets for many disorders. Functionally, M1, M3, and M5 mAChRs preferentially couple to Gq/11 proteins, whilst M2 and M4 mAChRs predominantly couple to Gi/o proteins. Both agonists and antagonists of mAChRs are clinically approved drugs, including pilocarpine for the treatment of elevated intra-ocular pressure and glaucoma, and atropine for the treatment of bradycardia and poisoning by muscarinic agents such as organophosphates.

Further reading on Acetylcholine receptors (muscarinic)

Burger WAC et al. (2018) Toward an understanding of the structural basis of allostery in muscarinic acetylcholine receptors. J Gen Physiol 150: 1360-1372 [PMID:30190312]

Caulfield MP et al. (1998) International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev 50: 279-90 [PMID:9647869]

Eglen RM. (2012) Overview of muscarinic receptor subtypes. Handb Exp Pharmacol 3-28 [PMID:22222692]

Kruse AC et al. (2014) Muscarinic acetylcholine receptors: novel opportunities for drug development. Nat Rev Drug Discov 13: 549-60 [PMID:24903776]

Leach K et al. (2012) Structure-function studies of muscarinic acetylcholine receptors. Handb Exp Pharmacol 29-48 [PMID:22222693]

Valant C et al. (2012) The best of both worlds? Bitopic orthosteric/allosteric ligands of g protein-coupled receptors. Annu Rev Pharmacol Toxicol 52: 153-78 [PMID:21910627]

Nomenclature M1 receptor M2 receptor
HGNC, UniProt CHRM1, P11229 CHRM2, P08172
Endogenous agonists acetylcholine [1051, 1152] acetylcholine [378, 1051, 1152]
Agonists xanomeline (Partial agonist) [409, 2504, 2562], methacholine [1835, 1984] – Rat, arecoline [1051, 1799, 1984], oxotremorine (Partial agonist) [1051, 1984], carbachol [409, 1051, 2562], pilocarpine (Partial agonist) [1051, 1984], bethanechol [1051, 1984], iperoxo [2097] iperoxo [2097, 2098], xanomeline [2504, 2562], methacholine [1835, 1984] – Rat, oxotremorine [1051, 1984], arecoline [1051, 1799, 1984], pilocarpine (Partial agonist) [1051, 1984], bethanechol [1051, 1984]
Antagonists tiotropium (pKi 9.6–10.7) [538, 1902, 2285, 2324], aclidinium (pIC50 10.1–10.2) [1902, 2324], glycopyrrolate (pIC50 9.6–10.1) [2241, 2285], ipratropium (pKi 9.3–9.8) [943, 1902], atropine (pKi 8.5–9.6) [409, 679, 943, 993, 1846, 2196], biperiden (pKd 9.3) [204], 4-DAMP (pKi 9.3) [555], darifenacin (pKi 8.9–9.1) [753, 943, 2180], scopolamine (pKi 9) [464, 993], oxybutynin (pKi 8.6) [511, 2180], tolterodine (pKi 8.4–8.5) [753, 2180], droxidopa (pKi 7.1) [464] tiotropium (pKi 9.9–10.7) [538, 1902, 2285, 2324], aclidinium (pIC50 10.1) [1902, 2324], ipratropium (pKi 9.3–9.8) [943, 1902], glycopyrrolate (pIC50 8.7–9.5) [2241, 2285], atropine (pKi 7.8–9.2) [464, 943, 993, 1846], scopolamine (pKi 8.7) [204, 993], tolterodine (Inverse agonist) (pKi 8.4–8.5) [753, 2180], 4-DAMP (pKi 8.4) [555], biperiden (pKd 8.2) [204], oxybutynin (pKi 7.9–8.1) [511, 2180], darifenacin (Inverse agonist) (pKi 7.2–7.3) [753, 943, 2180], tropicamide (pKi 7.2) [464]
Selective antagonists pirenzepine (pKi 7.6–8.3) [281, 555, 904, 993, 1086, 2526], VU0255035 (pKi 7.8) [2142] AFDX384 (pKi 8.1–8.2) [464, 555]
Allosteric modulators muscarinic toxin 7 (Negative) (pKi 11–11.1) [679, 1696, 1787], benzoquinazolinone 12 (Positive) (pKB 6.6) [6], KT 5720 (Positive) (pKd 6.4) [1310], brucine (Positive) (pKd 4.5–5.8) [180, 1051, 1309], BQCA (Positive) (pKB 4–4.8) [6, 7, 306, 1455], VU0029767 (Positive) [1511], VU0090157 (Positive) [1511] gallamine (Negative) (pKi 5.8–7.6) [1239, 1626, 2375], W-84 (Negative) (pKd 6–7.5) [1608, 2375], C7/3-phth (Negative) (pKd 7.1) [88, 410], alcuronium (Negative) (pKd 6.1–6.9) [88, 1051, 2375], gallamine (Negative) (pKd 5.9–6.3) [424, 1307], LY2119620 (Positive) (pKd 5.5–5.7) [465, 1253], LY2033298 (Positive) (pKd 4.4) [2408]
Labelled ligands [3H]QNB (Antagonist) (pKd 10.6–10.8) [1052, 1846], [3H]N-methyl scopolamine (Antagonist) (pKd 9.4–10.3) [336, 409, 411, 943, 1051, 1053, 1086, 1155, 1307], [3H]darifenacin (Selective Antagonist) (pKd 8.8) [2196], [3H]pirenzepine (Selective Antagonist) (pKd 7.9) [339, 2074, 2413, 2505] [3H]QNB (Antagonist) (pKd 10.1–10.6) [1052, 1846], [3H]N-methyl scopolamine (Antagonist) (pKd 9.3–9.9) [336, 943, 1052, 1053, 1155, 1307, 2492], [3H]AF DX-384 (Selective Antagonist) (pKd 9) [339, 1591, 2413]
Comments Atypical agonists: AC-42 [89, 1292, 1293, 2050, 2221, 2222], 77-LH-28-1 [89, 1292], N-desmethylclozapine [2050, 2221, 2272], TBPB [1089, 1152, 2050], McN-A-343 [1051, 1984] Atypical agonists: AC-42 [1292, 1537], 77-LH-28-1 [1292, 1537], N-desmethylclozapine [2272], McN-A-343 [1051, 1537, 1984]

Nomenclature M3 receptor M4 receptor M5 receptor
HGNC, UniProt CHRM3, P20309 CHRM4, P08173 CHRM5, P08912
Endogenous agonists acetylcholine [378, 1051, 1152] acetylcholine [1051, 1152] acetylcholine [378]
Agonists xanomeline (Partial agonist) [2504, 2562], methacholine [1835, 1984] – Rat, arecoline [1051, 1799, 1984], oxotremorine [1051, 1984], pilocarpine (Partial agonist) [1051, 1984], carbachol [378, 1051, 2562], bethanechol [1051, 1984], iperoxo [2097] xanomeline (Partial agonist) [2504, 2562], methacholine [1835, 1984] – Rat, arecoline [1051, 1799, 1984], oxotremorine [1051, 1984], pilocarpine (Partial agonist) [1051, 1984], carbachol [1051, 2562], bethanechol [1051, 1984], iperoxo [2097] xanomeline (Partial agonist) [793, 2504, 2562], pilocarpine (Partial agonist) [162, 548, 793], carbachol [162, 793, 2562], arecoline [1799, 1984], bethanechol [1984], iperoxo [2097], methacholine [1984]
Antagonists tiotropium (pKi 9.5–11.1) [538, 558, 1902, 2285, 2324], aclidinium (pKi 10.1–10.2) [1902, 2324], atropine (pKi 8.5–9.8) [464, 943, 993, 1846], glycopyrrolate (pIC50 9.6–9.8) [2241, 2285], ipratropium (pKi 9.3–9.8) [558, 943, 1902], scopolamine (pKi 9.4) [204, 993], 4-DAMP (pKi 9.3) [555], darifenacin (pKi 8.9–9.1) [753, 943, 2180], oxybutynin (pKi 8.8) [511, 2180], tolterodine (pKi 8.4–8.5) [753, 2180], biperiden (pKd 8.4) [204], tropicamide (pKi 7) [464] tiotropium (pKi 10.2–10.6) [2285, 2324], aclidinium (pKi 10) [2324], glycopyrrolate (pKi 9.1–10) [2241, 2285], atropine (pKi 8.7–9.5) [464, 943, 993, 1846], scopolamine (pKi 9.1–9.5) [204, 993], ipratropium (pKi 9.2) [943], 4-DAMP (pKi 8.9) [555], oxybutynin (pKi 8.4–8.7) [511, 2180], biperiden (pKd 8.6) [204], tolterodine (pKi 8.3–8.4) [753, 2180], darifenacin (pKi 7.3–8.1) [753, 943, 2180], tropicamide (pKi 6.9) [318] tiotropium (pKi 9.8–10.2) [2285, 2324], aclidinium (pKi 9.9) [2324], glycopyrrolate (pKi 8.9–9.9) [2241, 2285], atropine (pKi 8.3–9.3) [464, 943, 1645], 4-DAMP (pKi 9) [555], ipratropium (pKi 8.8) [943], tolterodine (pKi 8.5–8.8) [753, 2180], scopolamine (pKi 8.7) [204], darifenacin (pKi 7.9–8.6) [753, 943, 2180], biperiden (pKd 8.2) [204], oxybutynin (pKi 7.9) [511, 2180], tropicamide (pKi 6.4) [464]
Selective antagonists PCS1055 (pKi 8.2) [464], AFDX384 (pKi 7.3–8) [464, 555], PD 102807 (pKi 7.4–7.6) [464, 1788] ML381 (pKi 6.3) [732]
Allosteric modulators WIN 62,577 (Positive) (pKd 5.1) [1311], N-chloromethyl-brucine (Positive) (pKd 3.3) [1309] muscarinic toxin 3 (Negative) (pKi 8.7) [1086, 1786], VU0152100 (Positive) (pEC50 6.4) [239] – Rat, VU0152099 (Positive) (pEC50 6.4) [239] – Rat, LY2033298 (Positive) (pKB 4.9–5.5) [346, 2272], LY2119620 (Positive) (pKd 5.5) [465], thiochrome (Positive) (pKd 4) [1308] amiodarone (Positive) (pKB 7.2) [2229], ML380 (Positive) (pKB 4.8) [162, 734]
Selective allosteric modulators ML375 (Negative) (pKB 6.2–6.6) [733, 2458]
Labelled ligands [3H]QNB (Antagonist) (pKd 10.4) [1052, 1846], [3H]N-methyl scopolamine (Antagonist) (pKd 9.7–10.2) [336, 943, 1051, 1052, 1155, 1307], [3H]darifenacin (Selective Antagonist) (pKd 9.5) [2196], [3H]4-DAMP (Selective Antagonist) (pKi 8.8–9.4) [339, 1068] [3H]QNB (Antagonist) (pKd 9.7–10.5) [1052, 1845], [3H]N-methyl scopolamine (Antagonist) (pKd 9.9–10.2) [336, 1051, 1052, 1155, 1307, 2492], [3H]AF DX-384 (Selective Antagonist) (pKd 8.7) [339, 1591, 2413] [3 H]QNB (Antagonist) (pKd 10.2–10.7) [1052], [3 H]N-methyl scopolamine (Antagonist) (pKd 9.3–9.7) [336, 378, 943, 1052, 1155, 2458, 2492]
Comments Atypical agonists: AC-42 [1292], 77-LH-28-1 [1292], N-desmethylclozapine [2272], McN-A-343 [1051, 1984] Atypical agonists: AC-42 [1292], 77-LH-28-1 [1292], N-desmethylclozapine [2272], McN-A-343 [1051, 1984] Atypical agonists: AC-42 [1292], 77-LH-28-1 [1292], McN-A-343 [1984]

Comments

Atomic structures for all five mAChRs bound to antagonists [833, 2332, 2458, 2622], and structures of agonist-bound M2 mAChR [1253] and G protein-bound M1 and M2 mAChRs [1471] have been reported. These structures show that the orthosteric binding site of this family of receptor is absolutely conserved and, as a consequence, explain why highly selective orthosteric ligand binding to any specific mAChR has been notoriously difficult to achieve. As such, it is common to assess the rank order of affinity for a range of antagonists with limited selectivity (e.g., 4-DAMP, darifenacin, pirenzepine, AFDX384) to identify the involvement of particular subtypes. In addition, some ligands may display selectivity at the level of function(e.g., xanomeline) or binding kinetics (e.g., tiotropium) [2137, 2326].

Structures of the M1 and M2 mAChRs in complex with allosteric modulators [1253, 1472] have validated numerous pharmacological studies that indicated the presence of a common mAChR allosteric site located at the extracellular entrance to these receptors. Allosteric ligands proposed to bind to this common allosteric site include gallamine, strychnine, C7/3-phth, brucine and LY2033298. Additionally, a second allosteric site has been proposed on the mAChRs based on pharmacological analyses of the actions of compounds such as KT 5720, WIN 62,577, WIN 51,708, staurosporine and amiodarone [1310, 1311, 2229]. In the presence of the orthosteric ligand, allosteric modulators can exert positive, negative, or neutral cooperativity with that ligand. Direct receptor activation via an allosteric site has been reported for a number of allosteric ligands of the mAChRs [493, 1321, 1324, 1455, 1698, 1699]. ‘Atypical agonists’ are ligands that have been suggested to have bitopic binding modes for at least one subtype whereby the agonist occupies both the orthosteric and allosteric sites [89, 1151, 2409].

Adenosine receptors

Overview

Adenosine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adenosine Receptors [667]) are activated by the endogenous ligand adenosine(potentially inosine also at A3 receptors). Crystal structures for the antagonist-bound [436, 1038, 1421, 2119], agonist-bound [1329, 1330, 2591] and G protein-bound A2A adenosine receptors [317] have been described. The structures of an antagonist-bound A1 receptor [763] and an adenosine-bound A1 receptor-Gi complex [560] have been resolved by cryo-electronmicroscopy. Another structure of an antagonist-bound A1 receptor obtained with X-ray crystallography has also been reported [381]. Caffeine is a nonselective antagonist for adenosine receptors, while istradefylline, a selective A2A receptor antagonist, is on the market for the treatment of Parkinson’s disease.

Further reading on Adenosine receptors

Borea PA et al. (2015) The A3 adenosine receptor: history and perspectives. Pharmacol Rev 67: 74-102 [PMID:25387804]

Cronstein BN et al. (2017) Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases. Nat Rev Rheumatol 13: 41-51 [PMID:27829671]

Fredholm BB et al. (2011) International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors–an update. Pharmacol Rev 63: 1-34 [PMID:21303899]

Guo D et al. (2017) Kinetic Aspects of the Interaction between Ligand and G Protein-Coupled Receptor: The Case of the Adenosine Receptors. Chem Rev 117: 38-66 [PMID:27088232]

Göblyös A et al. (2011) Allosteric modulation of adenosine receptors. Biochim Biophys Acta 1808: 1309-18 [PMID:20599682]

Jacobson KA et al. (2020) Adenosine A2A receptor antagonists: from caffeine to selective non-xanthines. Br J Pharmacol [PMID:32424811]

Lasley RD. (2011) Adenosine receptors and membrane microdomains. Biochim Biophys Acta 1808: 1284-9 [PMID:20888790]

Mundell S et al. (2011) Adenosine receptor desensitization and trafficking. Biochim Biophys Acta 1808: 1319-28 [PMID:20550943]

Vecchio EA et al. (2018) New paradigms in adenosine receptor pharmacology: allostery, oligomerization and biased agonism. Br J Pharmacol 175: 4036-4046 [PMID:29679502]

Wei CJ et al. (2011) Normal and abnormal functions of adenosine receptors in the central nervous system revealed by genetic knockout studies. Biochim Biophys Acta 1808: 1358-79 [PMID:21185258]

Nomenclature A1 receptor A2A receptor A2B receptor A3 receptor
HGNC, UniProt ADORA1, P30542 ADORA2A, P29274 ADORA2B, P29275 ADORA3, P0DMS8
Endogenous agonists adenosine [2606] adenosine [665, 666, 2606] adenosine [665, 666, 2606] adenosine [665, 666, 2606]
Agonists NECA [704, 1080, 1996, 2373, 2606] NECA [223, 537, 704, 1172, 1267, 2606] NECA [172, 223, 1070, 1401, 2237, 2429, 2606] NECA [223, 704, 1047, 2049, 2430, 2606]
Selective agonists cyclopentyladenosine [471, 501, 704, 911, 1044, 1080, 1996], 5-Cl-5-deoxy-(±)-ENBA [661], TCPA [174], CCPA [1044, 1759], MRS7469 [2370] apadenoson [1836], UK-432,097 [824, 2591], compound 4g [436], CGS 21680 [223, 537, 704, 1044, 1172, 1202, 1267, 1759], regadenoson [1044] BAY 60-6583 [578] piclidenoson [632, 693, 1202, 2430], Cl-IB-MECA [240, 1047, 1169], MRS5698 [2369]
Antagonists CGS 15943 (pKi 8.5) [1790], xanthine amine congener (pKd 7.5) [661] CGS 15943 (pKi 7.7–9.4) [537, 1172, 1202, 1790], xanthine amine congener (pKi 8.4–9) [537, 1202] xanthine amine congener (pKi 6.9–8.8) [172, 1070, 1071, 1202, 1401, 2237], CGS 15943 (pKi 6–8.1) [80, 1070, 1071, 1202, 1790, 2237] CGS 15943 (pKi 7–7.9) [1178, 1202, 1790, 2430], xanthine amine congener (pKi 7–7.4) [1202, 2049, 2430]
Selective antagonists PSB36 (pKi 9.9) [8] – Rat, DPCPX (pKi 7.4–9.2) [501, 1022, 1759, 1996, 2530], derenofylline (pKi 9) [1110], WRC-0571 (pKi 8.8) [1514], DU172 (pKi 7.4) [763] SCH442416 (pKi 8.4–10.3) [2157, 2360], ZM-241385 (pKi 8.8–9.1) [1790] PSB-0788 (pKi 9.4) [222], PSB603 (pKi 9.3) [222], MRS1754 (pKi 8.8) [1070, 1177], PSB1115 (pKi 7.3) [895] MRS1220 (pKi 8.2–9.2) [1047, 1178, 2262, 2624], VUF5574 (pKi 8.4) [2418], MRS1523 (pKi 7.7) [1369], MRS1191 (pKi 7.5) [1047, 1073, 1382]
Allosteric modulators PD81723 (Positive) [275] LUF6000 (Positive) [767], LUF6096 (Positive) [910]
Labelled ligands [3H]CCPA (Agonist) [1202, 1996], [3H]DPCPX (Antagonist) (pKd 8.4–9.2) [471, 632, 1202, 1790, 1996, 2373] [3H]ZM 241385 (Antagonist) (pKd 8.7–9.1) [42, 702], [3H]CGS 21680 (Agonist) [1059, 2476] [3H]MRS1754 (Antagonist) (pKd 9.8) [1070] [125I]AB-MECA (Agonist) [1790, 2430]

Comments

Adenosine inhibits many intracellular ATP-utilising enzymes, including adenylyl cyclase (P-site). A pseudogene exists for the A2B adenosine receptor (ADORA2BP1) with 79% identity to the A2B adenosine receptor cDNA coding sequence, but which is unable to encode a functional receptor [1048]. DPCPX also exhibits antagonism at A2B receptors (pKi ca. 7, [40, 1202]). Antagonists at A3 receptors exhibit marked species differences, such that only MRS1523 and MRS1191 are selective at the rat A3 receptor. In the absence of other adenosine receptors, [3H]DPCPX and [3H]ZM 241385 can also be used to label A2B receptors(KD ca. 30 and 60 nM respectively). [125I]AB-MECA also binds to A1 receptors [1202]. [3H]CGS 21680 is relatively selective for A2A receptors, but may also bind to other sites in cerebral cortex [466, 1081]. [3H]NECA binds to other non-receptor elements, which also recognise adenosine [1435]. XAC-BY630 has been described as a fluorescent antagonist for labelling A1 adenosine receptors in living cells, although activity at other adenosine receptors was not examined [251].

Adhesion Class GPCRs

Overview

Adhesion GPCRs are structurally identified on the basis of a large extracellular region, similar to the Class B GPCR, but which is linked to the 7TM region by a GPCR autoproteolysis-inducing (GAIN) domain [62] containing a GPCR proteolytic site. The N-terminus often shares structural homology with adhesive domains (e.g. cadherins, immunolobulin, lectins) facilitating inter- and matricellular interactions and leading to the term adhesion GPCR [669, 2638]. Several receptors have been suggested to function as mechanosensors [233, 1861, 2094, 2545]. The nomenclature of these receptors was revised in 2015 as recommended by NC-IUPHAR and the Adhesion GPCR Consortium [845].

Further reading on Adhesion Class GPCRs

Hamann J et al. (2015) International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors. Pharmacol Rev 67: 338-67 [PMID:25713288]

Langenhan T et al. (2013) Sticky signaling–adhesion class G protein-coupled receptors take the stage. Sci Signal 6: re3 [PMID:23695165]

Liebscher I et al. (2016) Tethered Agonism: A Common Activation Mechanism of Adhesion GPCRs. Handb Exp Pharmacol 234: 111-125 [PMID:27832486]

Monk KR et al. (2015) Adhesion G Protein-Coupled Receptors: From In Vitro Pharmacology to In Vivo Mechanisms. Mol Pharmacol 88: 617-23 [PMID:25956432]

Purcell RH et al. (2018) Adhesion G Protein-Coupled Receptors as Drug Targets. Annu Rev Pharmacol Toxicol 58: 429-449 [PMID:28968187]

Nomenclature ADGRA1 ADGRA2 ADGRA3 ADGRB1 ADGRB2
HGNC, UniProt ADGRA1, Q86SQ6 ADGRA2, Q96PE1 ADGRA3, Q8IWK6 ADGRB1, O14514 ADGRB2, O60241
Endogenous agonists phosphatidylserine [1814]
Comments Required to assemble higher-order Reck/Gpr124/Frizzled/ Lrp5/6 complexes [612, 1895, 2412, 2426, 2683]. Interacts with Reck [394, 612, 2426], Syndecan-1, -2 [397], Integrin-αvβ3 [2411] and heparin [2411]. Principal signal transduction involves Dishevelled [612], β-catenin [1895] and Cdc42 [350]. Principal signal transduction involves Dishevelled [1376]. Reported to mediate phagocytosis through binding of phosphatidylserine [1814] and lipopolysaccharide [477]. Suppresses medulloblastoma formation [2684] and is involved in dendrite development [572]. A recent study disputes the previously reported expression of ADGRB1 by macrophages [987]. Principal signal transduction involves Gαz [1915]. A R1465W mutation confers increased coupling to Gαi [1915].

Nomenclature ADGRB3 CELSR1 CELSR2 CELSR3 ADGRD1 ADGRD2
Systematic nomenclature ADGRC1 ADGRC2 ADGRC3
HGNC, UniProt ADGRB3, O60242 CELSR1, Q9NYQ6 CELSR2, Q9HCU4 CELSR3, Q9NYQ7 ADGRD1, Q6QNK2 ADGRD2, Q7Z7M1
Endogenous agonists Peptides derived from the Stachel sequence: THLTNFAILMQVV [1388]
Comments Reported to bind C1q-like molecules [208]. Promotes myoblast fusion in vertebrates [849]. Principal signal transduction involves Rho kinase [1741]. Interacts with Vangl-2 [522, 1348], Frizzled-6 [522] and LRRK2 [2046]. Mutated in Joubert syndrome patients [2444]. Signal transduction is potentially mediated through Gαq/11 [2151]. Interacts homomerically with CELSR2/ADGRC2 [2151]. High-confidence risk gene for Tourette syndrome [2491]. Signal transduction is potentially mediated through Gαq/11 [2151]. Interacts with Frizzled-3 [2331], Dystroglycan [1402] and homomerically with CELSR3/ADGRC3 [2151]. Is a Gs protein-coupled receptor [200, 1388] and highly expressed in glioblastoma [133]. Couples also to Gi proteins [1389]. Strong association with body height [1173, 1180, 2365]. Associated with bone mineral density [2038].

Nomenclature ADGRE1 ADGRE2 ADGRE3 ADGRE4P ADGRE5 ADGRF1 ADGRF2
HGNC, UniProt ADGRE1, Q14246 ADGRE2, Q9UHX3 ADGRE3, Q9BY15 ADGRE4P, Q86SQ3 ADGRE5, P48960 ADGRF1, Q5T601 ADGRF2, Q8IZF7
Endogenous agonists Peptides derived from the Stachel sequence TSFSILMSPFVPSTIFPVVKWIT [515, 2246]
Comments A mutation destabilizing the GAIN domain sensitizes mast cells to IgE-independent vibration-induced degranulation [233]. Reported to bind chondroitin sulfate B [2228].Principal signal transduction involves G protein-coupling [175] and the phospholipase C pathway [1023]. Interacts with FHR1 [1023]. Reported to bind CD55 [846], chondroitin sulfate B [2228], α5β1 and αγβ3 integrins [2493], and CD90 [2478]. N-Docosahexaenoylethanolamine is an agonist at ADGRF1 supporting neurogenesis [1338] and couples to Gs and Gq pathways [515, 2246]. ADGRF2 is highly expressed in squamous epithelia and gene deficiency did not result in detectable defects [1910].

Nomenclature ADGRF3 ADGRF4 ADGRF5 ADGRG1
HGNC, UniProt ADGRF3, Q8IZF5 ADGRF4, Q8IZF3 ADGRF5, Q8IZF2 ADGRG1, Q9Y653
Endogenous agonists Peptides derived from the ADGRF5 (GPR116) Stachel sequence: TSFSILMSPDSPD [515] Peptides derived from the Stachel sequence: TSFSILMSPDSPD [515] Peptides derived from the Stachel sequence: TYFAVLM [2246]
Comments ADGRF3 is highly expressed in gastrointestinal neuroendocrine tumors [319, 319]. ADGRF4 couples to Gq/11 proteins [515], is highly expressed in squamous epithelia and gene deficiency did not result in detectable defects [1910]. ADGRF5 controls alveolar surfactant secretion via Gq/11 pathway [270, 515, 1204, 2320]. ADGRF5 deficiency leads to dysregulation of lung surfactant homeostasis [252, 686, 2617]. Reported to bind tissue transglutaminase 2 [2592] and collagen, which activates the G12/13 pathway [1448]. Interacts with heparin [387]. Couples to G13 proteins [2246]. 3-α-acetoxydihydrodeoxygedunin is a partial agonist [2247], Dihydromunduletone, a rotenoid derivative, is an antagonist [2245]. Negatively regulates immediate effector functions in human NK cells [349]. Deficiency leads to dysregulation of central and peripheral myelination [11, 749].

Nomenclature ADGRG2 ADGRG3 ADGRG4 ADGRG5
HGNC, UniProt ADGRG2, Q8IZP9 ADGRG3, Q86Y34 ADGRG4, Q8IZF6 ADGRG5, Q8IZF4
Endogenous agonists Peptides derived from the Stachel sequence: TSFGVLLDLSRTSLPP [514] Peptides derived from the Stachel sequence: TYFAVLMQLSGDPVPAEL [2245, 2545]
Comments ADGRG2 is coupled to Gq and Gs pathways [514, 2659] and gene deficiency causes congenital obstructive azoospermia [1822]. ADGRG3 is expressed in immune cells [2146, 2486] and couples to Go proteins [826], Gαs and Gαo/i signaling [986] and Gs proteins [986]. Binds to exogenous ligands beclomethasone dipropionate and cortisol [826, 1877]. ADGRG4 is highly expressed in enterochromaffin cells and gastrointestinal neuroendocrine tumors [1350]. ADGRG5 is a constitutively active Gs protein-coupled receptor [826, 2245, 2545], highly expressed in eosinophils and NK cells [1844]. Dihydromunduletone is an antagonist [2245].

Nomenclature ADGRG6 ADGRG7
HGNC, UniProt ADGRG6, Q86SQ4 ADGRG7, Q96K78
Endogenous agonists Peptides derived from the Stachel sequence: THFGVLMDLPRSASQL [1388]
Comments ADGRG6 is a key regulator of Schwann cell-mediated myelination [1619], and couples to Gs and Gi/o pathways [1388, 1606, 1861]. Apomorphine hydrochloride is an exogenous agonist [237]. Binds to Laminin-211 [1861]. ADGRG6 is essential for normal differentiation of promyelinating Schwann cells and for normal myelination of axons [1606, 1619, 1620, 1861] and for proper heart development [1826, 2470]. Further, conditional deletion of Adgrg6 revealed that this adhesion GPCR is involved in regulation of body length and bone mass [2264] and intervertebral disc function [1423]. Involved in arthrogryposis multiplex congenita (lethal congenital contracture syndrome-9) [1954]. ADGRG7 is expressed in intestine and involved in regulation of intestinal contractility [1727].

Nomenclature ADGRL1 ADGRL2 ADGRL3 ADGRL4 ADGRV1
HGNC, UniProt ADGRL1, O94910 ADGRL2, O95490 ADGRL3, Q9HAR2 ADGRL4, Q9HBW9 ADGRV1, Q8WXG9
Comments Couples to Gs and Gq pathways [1352, 1666]. Principal signal transduction involves Gαs [1666], Gαo [1352, 1933] and Gαq [1933]. Interacts with Teneurin-2 [2171], FLRT-1, -3 [1757], Neurexin-1α, -1β, -2β, -3β [226], Contactin-6 [2694], Shank [1246] and TRIP8b [1887, 1888]. A LPHN3 gene variant in humans is associated with attention-deficit-hyperactivity disorder [65, 2548]. Principal signal transduction involves Gα12/13 [1522] and Gαq [1522]. Interacts with Teneurin-3 [1757], FLRT-1, -3 [1757] and UNC5A [1040]. Loss-of-function mutations are associated with Usher syndrome, a sensory deficit disorder [1049]. Interacts with Harmonin [1966] and Whirlin [2422].

Adrenoceptors

Overview

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [295, 933].

Further reading on Adrenoceptors

Baker JG et al. (2011) Evolution of β-blockers: from anti-anginal drugs to ligand-directed signalling. Trends Pharmacol Sci 32: 227-34 [PMID:21429598]

Bylund DB et al. (1994) International Union of Pharmacology nomenclature of adrenoceptors. Pharmacol Rev 46: 121-36 [PMID:7938162]

Evans BA et al. (2010) Ligand-directed signalling at beta-adrenoceptors. Br J Pharmacol 159: 1022-38 [PMID:20132209]

Jensen BC et al. (2011) Alpha-1-adrenergic receptors: targets for agonist drugs to treat heart failure. J Mol Cell Cardiol 51: 518-28 [PMID:21118696]

Kobilka BK. (2011) Structural insights into adrenergic receptor function and pharmacology. Trends Pharmacol Sci 32: 213-8 [PMID:21414670]

Langer SZ. (2015) α2-Adrenoceptors in the treatment of major neuropsychiatric disorders. Trends Pharmacol Sci 36: 196-202 [PMID:25771972]

Michel MC et al. (2015) Selectivity of pharmacological tools: implications for use in cell physiology. A review in the theme: Cell signaling: proteins, pathways and mechanisms. Am J Physiol, Cell Physiol 308: C505-20 [PMID:25631871]

Adrenoceptors,α1

Overview

The threeα1-adrenoceptor subtypesα1A1B andα1D are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline.-(-) phenylephrine, methoxamine and cirazoline are agonists and prazosin and doxazosin antagonists considered selective forα1- relative toα2-adrenoceptors. [3H]prazosin and [125I]HEAT(BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin(Bodipy FLprazosin- QAPB) are used to examine cellular localisation ofα1-adrenoceptors.α1-Adrenoceptor agonists are used as nasal decongestants; antagonists to treat symptoms of benign prostatic hyperplasia (alfuzosin, doxazosin, terazosin, tamsulosin and silodosin, with the last two compounds beingα1A-adrenoceptor selective and claiming to relax bladder neck tone with less hypotension); and to a lesser extent hypertension (doxazosin, terazosin). Theα1- andβ2-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution ofα1-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs areα1-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension.

Nomenclature α1A-adrenoceptor α1B-adrenoceptor α1D-adrenoceptor
HGNC, UniProt ADRA1A, P35348 ADRA1B, P35368 ADRA1D, P25100
Endogenous agonists (-)-adrenaline [971, 2147], (-)-noradrenaline [971, 2147, 2322] (-)-noradrenaline [971, 2147], (-)-adrenaline [971, 2147]
Agonists oxymetazoline [971, 1760, 2147, 2322], phenylephrine [2322], methoxamine [2147, 2322] phenylephrine [655, 1594]
Selective agonists A61603 [655, 1203], dabuzalgron [193]
Antagonists prazosin (Inverse agonist) (pKi 9–9.9) [348, 472, 655, 2147, 2547], doxazosin (pKi 9.3) [853], terazosin (pKi 8.7) [1566], phentolamine (pKi 8.6) [2147], alfuzosin (pKi 8.1) [931] prazosin (Inverse agonist) (pKi 9.6–9.9) [655, 2147, 2547], tamsulosin (Inverse agonist) (pKi 9.5–9.7) [655, 2147, 2547], doxazosin (pKi 9.1) [853], alfuzosin (pKi 8.6) [932], terazosin (pKi 8.6) [1566], phentolamine (pKi 7.5) [2147] prazosin (Inverse agonist) (pKi 9.5–10.2) [655, 2147, 2547], tamsulosin (pKi 9.8–10.2) [655, 2147, 2547], doxazosin (pKi 9.1) [853], terazosin (pKi 9.1) [1566], alfuzosin (pKi 8.4) [931], dapiprazole (pKi 8.4) [84], phentolamine (Inverse agonist) (pKi 8.2) [2147], RS-100329 (pKi 7.9) [2547], labetalol (pKi 6.6) [84]
Selective antagonists tamsulosin (pKi 10–10.7) [348, 472, 655, 2147, 2547], silodosin (pKi 10.4) [2147], S(+)-niguldipine (pKi 9.1–10) [655, 2147], RS-100329 (pKi 9.6) [2547], SNAP5089 (pKi 8.8–9.4) [931, 1356, 2529], ρ-Da1a (pKi 9.2–9.3) [1479, 1928], RS-17053 (pKi 9.2–9.3) [348, 472, 654, 655] Rec 15/2615 (pKi 9.5) [2330], L-765314 (pKi 7.7) [1821], AH 11110 (pKi 7.5) [2067] BMY-7378 (pKi 8.7–9.1) [321, 2643]

Comments

The three α1-adrenoceptor subtypes areα1A1B and α1D. The previously describedα1C-adrenoceptor is a species homologue that corresponds to the pharmacologically definedα1A-adrenoceptor [933]. Some tissues possessα1A-adrenoceptors(termedα1L-adrenoceptors [655, 1644]) that display relatively low affinity in functional and binding assays for prazosin indicative of different receptor states or locations.α1A-Adrenoceptor C-terminal splice variants form homo- and heterodimers, and do not generate a functionalα1L-adrenoceptor [1944]. Recombinantα1D-adrenoceptors have been shown in some heterologous systems to be mainly located intracellularly but cell-surface localization is encouraged by truncation of the N-terminus, or by co-expression and formation of heterodimers withα1B1B- orβ2–β2-adrenoceptors [835, 2387]. In blood vessels all threeα1--adrenoceptor subtypes are located both at the cell surface and intracellularly [1564, 1565]. Signalling is predominantly via Gq/11 butα1-adrenoceptors also couple to Gi/o, Gs and G12/13. Severalα1A-adrenoceptor agonists display ligand directed signalling bias relative to noradrenaline [614] although some bias appears to relate to off-target activity [469]. There are also differences between subtypes in coupling efficiency to different pathways. In vascular smooth muscle, the potency of agonists is related to the predominant subtype,α1D- conveying greater agonist sensitivity compared toα1A-adrenoceptors [650].

Adrenoceptors,α2

Overview

The threeα2-adrenoceptor subtypesα2A2B andα2C are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. Brimonidine and talipexole are agonists and rauwolscine and yohimbine antagonists selective forα2- relative toα1-adrenoceptors. [3H]rauwolscine, [3H]brimonidine and [3H]RX821002 are relatively selective radioligands. There are species variations in the pharmacology of theα2A-adrenoceptor. Multiple mutations ofα2-adrenoceptors have been described, some associated with alterations in function. Presynapticα2-adrenoceptors regulate many functions in the nervous system. Theα2-adrenoceptor agonists clonidine, guanabenz and brimonidine affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. Clonidine is an anti-hypertensive (relatively little used) and counteracts opioid withdrawal. Dexmedetomidine (also xylazine) is increasingly used as a sedative and analgesic in human [119] and veterinary medicine and has sympatholytic and anxiolytic properties. Theα2-adrenoceptor antagonist mirtazapine is used as an anti-depressant. Theα2B subtype appears to be involved in neurotransmission in the spinal cord andα2C in regulating catecholamine release from adrenal chromaffin cells. Although subtype-selective antagonists have been developed, none are used clinically and they remain experimental tools.

Nomenclature α2A-adrenoceptor α2B-adrenoceptor α2C-adrenoceptor
HGNC, UniProt ADRA2A, P08913 ADRA2B, P18089 ADRA2C, P18825
Endogenous agonists (-)-adrenaline [1061, 1869], (-)-noradrenaline [1061, 1869] (-)-noradrenaline (Partial agonist) [1061, 1869], (-)-adrenaline [1061] (-)-noradrenaline [1061, 1869], (-)-adrenaline [1061]
Agonists dexmedetomidine (Partial agonist) [1061, 1460, 1840, 1869], clonidine (Partial agonist) [1061, 1840, 1869], brimonidine [1061, 1460, 1840, 1869], apraclonidine [1668], guanabenz [84], guanfacine (Partial agonist) [1061, 1463] dexmedetomidine [1061, 1460, 1840, 1869], clonidine (Partial agonist) [1061, 1840, 1869], brimonidine (Partial agonist) [1061, 1840, 1869], guanabenz [84], guanfacine [1061] dexmedetomidine [1061, 1840, 1869], brimonidine (Partial agonist) [1061, 1460, 1840, 1869], apraclonidine [1668], guanfacine (Partial agonist) [1061], guanabenz [84]
Selective agonists oxymetazoline (Partial agonist) [1061, 1460, 2391]
Antagonists yohimbine (pKi 8.4–9.2) [294, 521, 2391] yohimbine (pKi 7.9–8.9) [294, 521, 2391], phenoxybenzamine (pKi 8.5) [2512], tolazoline (pKi 5.5) [1061] yohimbine (pKi 8.5–9.5) [294, 521, 2391], WB 4101 (pKi 8.4–9.4) [294, 521, 2391], spiroxatrine (pKi 9) [2391], mirtazapine (pKi 7.7) [633], tolazoline (pKi 5.4) [1061]
Selective antagonists BRL 44408 (pKi 8.2–8.8) [2391, 2645] imiloxan (pKi 7.3) [1575] – Rat JP1302 (pKB 7.8) [2047]
Labelled ligands [3H]MK-912 (Antagonist) (pKd 10.1) [2391]

Comments

The threeα2-adrenoceptor subtypes are termedα2A2B andα2C. ARC-239 and prazosin show some selectivity forα2B- andα2C-adrenoceptors overα2A-adrenoceptors. Oxymetazoline is an imidazoline partial agonist that also binds to non-GPCR binding sites for imidazolines, classified as I1, I2 and I3 [474] at which catecholamines have a low affinity, while rilmenidine and moxonidine are selective ligands with hypotensive effects in vivo. I1-imidazoline recognition sites cause central inhibition of sympathetic tone, I2-imidazoline sites are an allosteric binding site on monoamine oxidase B, and I3-imidazoline sites regulate insulin secretion from pancreatic β-cells.α2A-adrenoceptor stimulation reduces insulin secretion from β-islets [2614], with a polymorphism in the 5’-UTR of the ADRA2A gene being associated with increased receptor expression inβ-islets and heightened susceptibility to diabetes [2008]. Theα2A- andα2C-adrenoceptors form homodimers [2192]. Heterodimers betweenα2A- and either theα2c-adrenoceptor or μ opioid peptide receptor exhibit altered signalling and trafficking properties compared to the individual receptors [2192, 2315, 2443]. Signalling byα2-adrenoceptors is primarily via Gi/o, although theα2A-adrenoceptor also couples to Gs [577]. Imidazoline compounds display bias relative to each other at theα2A-adrenoceptor [1830]. The noradrenaline reuptake inhibitor desipramine acts directly onα2A-adrenoceptors to promote internalisation via recruitment ofβ-arrestin [448]. The structure of theα2B-adrenoceptor has recently been determined by cryo-EM in complex with dexmedetomidine and Gαo at a resolution of 2.9 Åproviding insights into the structural requirements required for interactions withα2-adrenoceptor agonists [2648].

Adrenoceptors,β

Overview

The three β-adrenoceptor subtypesβ12 andβ3 are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for β-adrenoceptors relative toα1- andα2-adrenoceptors, while propranolol(pKi 8.2-9.2) and cyanopindolol (pKi 10.0-11.0) are relatively selective antagonists forβ1- andβ2- relative toβ3-adrenoceptors. (-)-noradrenaline, xamoterol and (-)-Ro 363 show selectivity forβ1- relative toβ2-adrenoceptors. Pharmacological differences exist between human and mouseβ3-adrenoceptors, and the ’rodent selective’ agonists BRL 37344 and CL316243 have low efficacy at the humanβ3-adrenoceptor whereas CGP 12177 (low potency) and L 755507 activate humanβ3-adrenoceptors[88].β3-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupranolol. SR59230A has reasonably high affinity atβ3-adrenoceptors, but does not discriminate between the three β- subtypes [1577] whereas L-748337 is more selective.[125I]- cyanopindolol,[125I]-hydroxy benzylpindolol and[3H]- alprenolol are high affinity radioligands that labelβ1- andβ2- adrenoceptors andβ3-adrenoceptors can be labelled with higher concentrations (nM) of[125I]- cyanopindolol together withβ1- andβ2-adrenoceptor antagonists. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to trackβ-adrenoceptors at the cellular level [8]. Somewhat selectiveβ1-adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival.β1-Adrenoceptor-preferring antagonists are used to treat cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol) but also in combination with other treatments to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol) [2558]. Cardiac failure is also treated with carvedilol that blocksβ1- andβ2-adrenoceptors, as well asα1-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) actingβ2-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generationβ-adrenoceptor antagonists (propranolol) block bothβ1- andβ2-adrenoceptors and there are noβ2-adrenoceptor-selective antagonists used therapeutically. Theβ3-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome. There is evidence to suggest thatβ-adrenoceptor antagonists can reduce metastasis in certain types of cancer [937].

Nomenclature β1-adrenoceptor β2-adrenoceptor β3-adrenoceptor
HGNC, UniProt ADRB1, P08588 ADRB2, P07550 ADRB3, P13945
Potency order of endogenous ligands (-)-noradrenaline> (-)-adrenaline (-)-adrenaline> (-)-noradrenaline (-)-noradrenaline = (-)-adrenaline
Endogenous agonists (-)-adrenaline [676, 956], (-)-noradrenaline [676, 956], noradrenaline [676] (-)-adrenaline [676, 956, 1058], (-)-noradrenaline [676, 956] (-)-noradrenaline [956, 1889, 2250], (-)-adrenaline [956]
Agonists pindolol (Partial agonist) [1254], isoprenaline [676, 2066], dobutamine (Partial agonist) [1029] pindolol (Partial agonist) [1254], arformoterol [43], isoprenaline [2066], ephedrine (Partial agonist) [1058] carazolol [1561]
Selective agonists (-)-Ro 363 [1610], xamoterol (Partial agonist) [1029], denopamine (Partial agonist) [1029, 2277] formoterol [103], salmeterol [103], zinterol [103], vilanterol [1906], procaterol [103], indacaterol [134], fenoterol [68], salbutamol (Partial agonist) [104, 1029], terbutaline (Partial agonist) [104], orciprenaline [2217] L 755507 [103], L742791 [2509], mirabegron [2301], CGP 12177 (Partial agonist) [191, 1436, 1561, 1610], SB251023 [1007] – Mouse, BRL 37344 [191, 543, 956, 1561], CL316243 [2611]
Antagonists carvedilol (pKi 9.5) [307], bupranolol (pKi 7.3–9) [307, 1436], SR59230A (pKi 8.6) [307], levobunolol (pKi 8.4) [84], labetalol (pKi 8.2) [84], metoprolol (pKi 7–7.6) [104, 307, 956, 1436], esmolol (pKi 6.9) [84], nadolol (pKi 6.9) [307], practolol (pKi 6.1–6.8) [104, 1436], propafenone (pKi 6.7) [84], sotalol (pKi 6.1) [84] carvedilol (pKi 9.4–9.9) [104, 307], timolol (pKi 9.7) [104], propranolol (pKi 9.1–9.5) [104, 106, 1029, 1436], SR59230A (pKi 9.3) [307], levobunolol (pKi 9.3) [84], bupranolol (pKi 8.3–9.1) [307, 1436], alprenolol (pKi 9) [104], nadolol (pKi 7–8.6) [104, 307], labetalol (pKi 8) [84], propafenone (pKi 7.4) [84], sotalol (pKi 6.5) [84] SR59230A (pKi 6.9–8.4) [307, 502, 956], bupranolol (pKi 6.8–7.3) [191, 307, 1436, 1561], propranolol (pKi 6.3–7.2) [1436, 1889], levobunolol (pKi 6.8) [1889]
Selective antagonists CGP 20712A (pKi 8.5–9.2) [104, 307, 1436], levobetaxolol (pKi 9.1) [2140], betaxolol (pKi 8.8) [1436], nebivolol (pIC50 8.1–8.7) [1829] – Rabbit, atenolol (pKi 6.7–7.6) [104, 1096, 1436], acebutolol (pKi 6.4) [84] ICI 118551 (Inverse agonist) (pKi 9.2–9.5) [104, 106, 1436] L-748337 (pKi 8.4) [307], L748328 (pKi 8.4) [307]
Allosteric modulators AS408 [1422]
Labelled ligands [125I]ICYP (Antagonist) (pKd 10.4–11.3) [1029, 1436, 2066] [125I]ICYP (Antagonist) (pKd 11.1) [1436, 2066] [125I]ICYP (Agonist, Partial agonist) [1436, 1610, 1889, 2066, 2250]
Comments The agonists indicated have less than two orders of magnitude selectivity [103]. Agonist SB251023 has a pEC50 of 6.9 for the splice variant of the mouse β3 receptor, β3b [1007].

Comments

The three β-adrenoceptors are termedβ12 andβ3. [125I]ICYP can be used to define eitherβ1- orβ2-adrenoceptors when conducted in the presence of aβ1- or aβ2-adrenoceptor-selective antagonist. A fluorescent analogue of CGP 12177 is used to study β-adrenoceptors in living cells [107]. [125I]ICYP at higher (nM) concentrations has been used to labelβ3-adrenoceptors in systems with few if any otherβ-adrenoceptor subtypes. Theβ3-adrenoceptor has an intron in the coding region, but splice variants have only been described for the mouse [615], where the isoforms display different signalling characteristics [1007]. There are threeβ-adrenoceptors in turkey (termed the tβ, tβ3c and tβ4c) with pharmacology that differs from the human β-adrenoceptors [105]. Numerous polymorphisms have been described for the β-adrenoceptors; some are associated with altered signalling and trafficking, susceptibility to disease and/or altered responses to pharmacotherapy [1390]. Allβ-adrenoceptors couple to Gs (activating adenylyl cyclase and elevating cAMP levels), but theβ2- andβ3-adrenoceptors in particular can also activate Gi and theβ2-adrenoceptor activates β-arrestin-mediated signalling. Manyβ1- andβ2-adrenoceptor antagonists are agonists atβ3-adrenoceptors (CL316243, CGP 12177 and carazolol). Many ‘antagonists’ of cAMP accumulation, for example carvedilol and bucindolol, weakly activate MAP kinase pathways [108, 616, 690, 691, 2064, 2065] and thus display biased agonism. Bupranolol acts as a neutral antagonist in most systems so far examined. Agonists also display biased signalling at theβ2-adrenoceptor via Gs or arrestins [559]. X-ray crystal structures have been described of the agonist bound [2496] and antagonist bound forms of theβ1- [2497], agonist-bound [383] and antagonist-bound forms of theβ2-adrenoceptor [1949, 2007], as well as a fully active agonist-bound, Gs protein-coupledβ2-adrenoceptor [1950], as well as providing insights into the structural requirements for agonist, partial agonist, antagonist, G protein andβ-arrestin coupling [2513]. Structures have also been described for negative allosteric modulators of theβ2-adrenoceptor [1422]. Cryo-EM studies have also been recently described that provide a structural framework for agonist mediated signal transduction [2253]. The agonists carvedilol and bucindolol bind to a site on theβ1-adrenoceptor involving contacts in TM2, 3, and 7 and extracellular loop 2 that may facilitate coupling to arrestins [2497]. Compounds displayingβ-arrestin-biased signalling at theβ2-adrenoceptor have a greater effect on the conformation of TM7, whereas full agonists for Gs coupling promote movement of TM5 and TM6 [1416]. Recent studies using NMR spectroscopy demonstrate significant conformational flexibility in theβ2-adrenoceptor that is stabilized by both agonist and G proteins highlighting the dynamic nature of interactions with both ligand and downstream signalling partners [1175, 1495, 1755]. Such flexibility likely has consequences for our understanding of allosterism and biased agonism, and for the future therapeutic exploitation of these phenomena.

Angiotensin receptors

Overview

The actions of angiotensin II (AGT, P01019) (Ang II) are mediated by AT1 and AT2 receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Angiotensin receptors [497, 1123]), which have around 30% sequence similarity. The decapeptide angiotensin I (AGT, P01019), the octapeptide angiotensin II (AGT, P01019) and the heptapeptide angiotensin III (AGT, P01019) are endogenous ligands. Losartan, candesartan, telmisartan, etc. are clinically used AT1 receptor blockers.

Further reading on Angiotensin receptors

Asada H et al. (2020) The Crystal Structure of Angiotensin II Type 2 Receptor with Endogenous Peptide Hormone. Structure 28: 418-425.e4 [PMID:31899086]

Karnik SS et al. (2015) International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli [corrected]. Pharmacol Rev 67: 754-819 [PMID:26315714]

Singh KD et al. (2019) Mechanism of Hormone Peptide Activation of a GPCR: Angiotensin II Activated State of AT1R Initiated by van der Waals Attraction. J Chem Inf Model 59: 373-385 [PMID:30608150]

Suomivuori CM et al. (2020) Molecular mechanism of biased signaling in a prototypical G protein-coupled receptor. Science 367: 881-887 [PMID:32079767]

Wingler LM et al. (2019) Distinctive Activation Mechanism for Angiotensin Receptor Revealed by a Synthetic Nanobody. Cell 176: 479-490.e12 [PMID:30639100]

Wingler LM et al. (2020) Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR. Science 367: 888-892 [PMID:32079768]

Nomenclature AT1 receptor AT2 receptor
HGNC, UniProt AGTR1, P30556 AGTR2, P50052
Endogenous agonists angiotensin II (AGT, P01019) [498, 2424], angiotensin III (AGT, P01019) [498], angiotensin IV (AGT, P01019) (Partial agonist) [1318] angiotensin III (AGT, P01019) [459, 498, 2533], angiotensin II (AGT, P01019) [498, 2203, 2533], angiotensin-(1-7) (AGT, P01019) [224]
Agonists [Sar1,Cha4]Ang-II [961, 1599] – Rat
Selective agonists L-162,313 [1851], L-163,101 [2398] CGP42112 [224], [p-aminoPhe6]ang II [498, 2224] – Rat, compound 21 [2440]
Antagonists saprisartan (pKi 9.1) [934] – Rat, 5-oxo-1-2-4-oxadiazol biphenyl (pIC50 8.8) [1730] – Rat, 5-butyl-methyl immidazole carboxylate 30 (pIC50 8.5) [19], LY303336 (pIC50 8.3) [2425], TRV027 (pKd 7.7) [2446] saralasin (pIC50 9) [392] – Rat
Selective antagonists candesartan (pIC50 9.5–9.7) [2424], eprosartan (pIC50 8.4–8.8) [582], losartan (pIC50 7.4–8.7) [498, 2356], telmisartan (pIC50 8.4) [1546], olmesartan (pIC50 8.1) [1218] PD123177 (pIC50 8.5–9.5) [352, 392, 569] – Rat, olodanrigan (pIC50 8.5–9.3) [640, 1981, 2201], PD123319 (pKd 8.7–9.2) [498, 568, 2543]
Labelled ligands [3H]candesartan (Antagonist) (pKd 10.3) [635], [125I][Sar1]Ang-II (Agonist) [631] – Rat, [125I][Sar1,Ile8]Ang-II (Agonist, Partial agonist) [631] – Rat, [3H]eprosartan (Antagonist) (pKd 9.1) [28] – Rat, [3H]losartan (Antagonist) (pKd 8.2) [356] – Rat [125I]CGP42112 (Agonist) [498, 2533, 2534], [125I][Sar1,Ile8]Ang-II (Agonist) [2313] – Rat
Comments Telmisartan and candesartan are also reported to be agonists of PPARγ [2244].

Comments

AT1 receptors are predominantly coupled to Gq/11, however they are also linked to arrestin recruitment and stimulate G protein-independent arrestin signalling [1452]. Most species express a single AGTR1 gene, but two related agtr1a and agtr1b receptor genes are expressed in rodents. The AT2 receptor counteracts several of the growth responses initiated by the AT1 receptors. The AT2 receptor is much less abundant than the AT1 receptor in adult tissues and is upregulated in pathological conditions. AT1 receptor antagonists bearing substituted 4-phenylquinoline moieties have been synthesized, which bind to AT1 receptors with nanomolar affinity and are slightly more potent than losartan in functional studies [310]. The antagonist activity of CGP42112 at the AT2 receptor has also been reported [2]. The AT1 and bradykinin B2 receptors have been proposed to form a heterodimeric complex [5].β-Arrestin1 prevents AT1-B2 receptor heteromerization [1929]. There is also evidence for an AT4 receptor that specifically binds angiotensin IV (AGT, P01019) and is located in the brain and kidney. An additional putative endogenous ligand for the AT4 receptor has been described (LVV-hemorphin (HBB, P68871), a globin decapeptide) [1605]. The crystal structure coordinates of AngII bound AT1R (PDB id: 6os0) and AT2R(PDB id: 6jod) [76] have been recently deposited in the protein structure database.

Apelin receptor

Overview

The apelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the apelin receptor [1879] and subsequently updated [1960]) responds to apelin, a 36 amino-acid peptide derived initially from bovine stomach. Apelin-36 (APLN, Q9ULZ1), apelin-13 (APLN, Q9ULZ1) and [Pyr1]apelin-13 (APLN, Q9ULZ1) are the predominant endogenous ligands which are cleaved from a 77 amino-acid precursor peptide (APLN, Q9ULZ1) by a so far unidentified enzymatic pathway [2325]. A second family of peptides discovered independently and named Elabela [393] or Toddler, that has little sequence similarity to apelin, is present, and functional at the apelin receptor in the adult cardiovascular system [1828, 2619]. Structure-activity relationship Elabela analogues have been described [1678].

Further reading on Apelin receptor

Cheng B et al. (2012) Neuroprotection of apelin and its signaling pathway. Peptides 37: 171-3 [PMID:22820556]

Langelaan DN et al. (2009) Structural insight into G-protein coupled receptor binding by apelin. Biochemistry 48: 537-48 [PMID:19123778]

Mughal A et al. (2018) Vascular effects of apelin: Mechanisms and therapeutic potential. Pharmacol Ther 190: 139-147 [PMID:29807055]

O’Carroll AM et al. (2013) The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis. J Endocrinol 219: R13-35 [PMID:23943882]

Pitkin SL et al. (2010) International Union of Basic and Clinical Pharmacology. LXXIV. Apelin receptor nomenclature, distribution, pharmacology, and function. Pharmacol Rev 62: 331-42 [PMID:20605969]

Read C et al. (2019) International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand. Pharmacol Rev 71: 467-502 [PMID:31492821]

Yang P et al. (2015) Apelin, Elabela/Toddler, and biased agonists as novel therapeutic agents in the cardiovascular system. Trends Pharmacol Sci 36: 560-7 [PMID:26143239]

Nomenclature apelin receptor
HGNC, UniProt APLNR, P35414
Potency order of endogenous ligands [Pyr1]apelin-13 (APLN, Q9ULZ1) ≥ apelin-13 (APLN, Q9ULZ1) > apelin-36 (APLN, Q9ULZ1) [622, 2325]
Endogenous agonists apelin-13 (APLN, Q9ULZ1) [622, 976, 1558], apelin receptor early endogenous ligand (APELA, P0DMC3) [516], apelin-17 (APLN, Q9ULZ1) [587, 1558], [Pyr1]apelin-13 (APLN, Q9ULZ1) [1134, 1558], Elabela/Toddler-21 (APELA, P0DMC3) [2618], Elabela/Toddler-32 (APELA, P0DMC3) [2618], apelin-36 (APLN, Q9ULZ1) [622, 976, 1134, 1558], Elabela/Toddler-11 (APELA, P0DMC3) [2618]
Selective agonists CMF-019 (Biased agonist) [1959], MM07 (Biased agonist) [241]
Antagonists MM54 (pKi 8.2) [1459]
Labelled ligands [125I][Nle75,Tyr77]apelin-36 (human) (Agonist) [1134], [125I][Glp65Nle75,Tyr77]apelin-13 (Agonist) [976], [125I](Pyr1)apelin-13 (Agonist) [1128], [125I]apelin-13 (Agonist) [622], [3H](Pyr1)[Met(0)11]-apelin-13 (Agonist) [1558]

Comments

Potency order determined for heterologously expressed human apelin receptor(pD2 values range from 9.5 to 8.6). The apelin receptor may also act as a co-receptor with CD4 for isolates of human immunodeficiency virus, with apelin blocking this function [335]. A modified apelin-13 peptide, apelin-13(F13A) was reported to block the hypotensive response to apelin in rat in vivo [1335], however, this peptide exhibits agonist activity in HEK293 cells stably expressing the recombinant apelin receptor [622]. The apelin receptor antagonist, MM54, was reported to suppress tumour growth and increase survival in an intracranial xenograft mouse model of glioblastoma [867].

Bile acid receptor

Overview

The bile acid receptor (GPBA) responds to bile acids produced during the liver metabolism of cholesterol. Selective agonists are promising drugs for the treatment of metabolic disorders, such as type II diabetes, obesity and atherosclerosis.

Further reading on Bile acid receptor

Duboc H et al. (2014) The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig Liver Dis 46: 302-12 [PMID:24411485]

Lefebvre P et al. (2009) Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 89: 147-91 [PMID:19126757]

Lieu T et al. (2014) GPBA: a GPCR for bile acids and an emerging therapeutic target for disorders of digestion and sensation. Br J Pharmacol 171: 1156-66 [PMID:24111923]

van Nierop FS et al. (2017) Clinical relevance of the bile acid receptor TGR5 in metabolism. Lancet Diabetes Endocrinol 5: 224-233 [PMID:27639537]

Nomenclature GPBA receptor
HGNC, UniProt GPBAR1, Q8TDU6
Potency order of endogenous ligands lithocholic acid> deoxycholic acid> chenodeoxycholic acid, cholic acid [1133, 1519]
Selective agonists S-EMCA [1838] – Mouse, betulinic acid [728], oleanolic acid [2063]

Comments

The triterpenoid natural product betulinic acid has also been reported to inhibit inflammatory signalling through the NFκB pathway [2293]. Disruption of GPBA expression is reported to protect from cholesterol gallstone formation [2435]. A new series of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides have been reported as highly potent agonists [1429].

Bombesin receptors

Overview

Mammalian bombesin (Bn) receptors comprise 3 subtypes: BB1, BB2, BB3 (nomenclature recommended by the NC-IUPHAR Subcommittee on bombesin receptors, [1066]). BB1 and BB2 are activated by the endogenous ligands neuromedin B (NMB, P08949)(NMB), gastrin-releasing peptide (GRP, P07492)(GRP), and GRP-(18-27) (GRP, P07492). Bombesin is a tetra-decapeptide, originally derived from amphibians. The three Bn receptor subtypes couple primarily to the Gq/11 and G12/13 family of G proteins [1066]. Each of these receptors is widely distributed in the CNS and peripheral tissues [774, 1066, 1890, 1942, 2058, 2662]. Activation of BB1 and BB2 receptors causes a wide range of physiological/pathophysiogical actions, including the stimulation of normal and neoplastic tissue growth, smooth-muscle contraction, gastrointestinal motility, feeding behavior, secretion and many central nervous system effects including regulation of circadian rhythm, body temperature control, sighing and mediation of pruritus [373, 689, 1066, 1374, 1629, 1637, 1923, 1942, 2268, 2475]. A physiological role for the BB3 receptor has yet to be fully defined although recently studies suggest an important role in glucose and insulin regulation, metabolic homeostasis, feeding, regulation of body temperature, obesity, diabetes mellitus and growth of normal/neoplastic tissues [774, 1373, 1483, 1635, 1769, 2582]. Bn receptors are one of the most frequently overexpressed receptors in cancers and are receiving increased attention for their roles in tumor growth, as well as for tumour imaging and for receptor targeted cytotoxicity [115, 1480, 1637, 2051].

Further reading on Bombesin receptors

Chen XJ et al. (2020) Central circuit mechanisms of itch. Nat Commun 11: 3052 [PMID:32546780]

González N et al. (2015) Bombesin receptor subtype 3 as a potential target for obesity and diabetes. Expert Opin Ther Targets 19: 1153-70 [PMID:26066663]

Jensen RT et al. (2008) International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states. Pharmacol Rev 60: 1-42 [PMID:18055507]

Li M et al. (2019) Bombesin Receptor Subtype-3 in Human Diseases. Arch Med Res 50: 463-467 [PMID:31911345]

Maina T et al. (2017) Theranostic Prospects of Gastrin-Releasing Peptide Receptor-Radioantagonists in Oncology. PET Clin 12: 297-309 [PMID:28576168]

Moreno P et al. (2016) Bombesin related peptides/receptors and their promising therapeutic roles in cancer imaging, targeting and treatment. Expert Opin Ther Targets 20: 1055-73 [PMID:26981612]

Qu X et al. (2018) Recent insights into biological functions of mammalian bombesin-like peptides and their receptors. Curr Opin Endocrinol Diabetes Obes 25: 36-41 [PMID:29120926]

Ramos-Álvarez I et al. (2015) Insights into bombesin receptors and ligands: Highlighting recent advances. Peptides 72: 128-44 [PMID:25976083]

Nomenclature BB1 receptor BB2 receptor BB3 receptor
HGNC, UniProt NMBR, P28336 GRPR, P30550 BRS3, P32247
Endogenous agonists neuromedin B (NMB, P08949) [1066, 1942, 2389] neuromedin C [2389], gastrin releasing peptide(14-27) (human) [2389], gastrin-releasing peptide (GRP, P07492) [156, 2032, 2389]
Selective agonists [D-Tyr6,β-Ala11,N-Me-Ala13,Nle14]bombesin-(6-14) [970] compound 9g [1527, 1943], MK-7725 [395], MK-5046 [1636, 2112], [D-Tyr6,Apa-4Cl11,Phe13,Nle14]bombesin-(6-14) [1500], compound 17c [1526], bag-1 [814], compound 22e [899]
Antagonists D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Nal-NH2 (pIC50 6.2–6.6) [773] BAY86-7548 (pIC50 8.6) [1104, 2389]
Selective antagonists PD 176252 (pIC50 9.3–9.8) [773], PD 168368 (pIC50 9.3–9.6) [773], dNal-cyc(Cys-Tyr-dTrp-Orn-Val)-Nal-NH2 [D-Phe6, Leu13, Cpa14,ψ13-14]bombesin-(6-14) (pKi 9.8) [773], JMV641 (pIC50 9.3) [2361] – Mouse, [(3-Ph-Pr6), His7,D-Ala11,D-Pro13,ψ13-14),Phe14]bombesin-(6-14) (pIC50 9.2) [773, 1328], JMV594 (pIC50 8.9) [1424, 2361] – Mouse, [D-Tpi6, Leu13 ψ(CH2NH)-Leu14]bombesin-(6-14) (pIC50 8.9) [773] bantag-1 (pIC50 8.6–8.7) [814, 1636, 1941], ML-18 (pIC50 5.3) [1628]
Labelled ligands [125I]BH-NMB (human, mouse, rat) (Agonist), [125I][Tyr4]bombesin (Agonist) [125I][D-Tyr6]bombesin-(6-13)-methyl ester (Selective Antagonist) (pKd 9.3) [1499] – Mouse, [125I][Tyr4]bombesin (Agonist) [156], [125I]GRP (human) (Agonist) [125I]bantag-1 (Selective Antagonist) (pKi 9.6) [1941], [3H]bag-2 (Agonist) [814] – Mouse, [125I][D-Tyr6,β-Ala11,Phe13,Nle14]bombesin-(6-14) (Agonist) [1501, 1636]

Comments

All three human subtypes may be activated by [D-Phe6,β-Ala11,Phe13,Nle14]bombesin-(6-14) [1501]. Agonists[D-Tyr6,Apa-4Cl11,Phe13,Nle14]bombesin-(6-14) has more than 200-fold selectivity for BB3 receptors over BB1 and BB2 [1500, 1501, 1942, 1942, 1943].

Bradykinin receptors

Overview

Bradykinin (or kinin) receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Bradykinin(kinin) Receptors [1342]) are activated by the endogenous peptides bradykinin (KNG1, P01042) (BK), [des-Arg9]bradykinin (KNG1, P01042), Lys-BK (kallidin (KNG1, P01042)), [des-Arg10]kallidin (KNG1, P01042),[Phospho-Ser6]-Bradykinin, T-kinin (KNG1, P01042) (Ile-Ser-BK), [Hyp3]bradykinin (KNG1, P01042) and Lys-[Hyp3]-bradykinin (KNG1, P01042). Variation in pharmacology and activity of B1 and B2 receptor antagonists at species orthologs has been documented. Icatibant (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema.

Further reading on Bradykinin receptors

Blaes N et al. (2013) Targeting the ’Janus face’ of the B2-bradykinin receptor. Expert Opin Ther Targets 17: 1145-66 [PMID:23957374]

Campos MM et al. (2006) Non-peptide antagonists for kinin B1 receptors: new insights into their therapeutic potential for the management of inflammation and pain. Trends Pharmacol Sci 27: 646-51 [PMID:17056130]

Couture R et al. (2014) Kinin receptors in vascular biology and pathology. Curr Vasc Pharmacol 12: 223-48 [PMID:24568157]

Paquet JL et al. (1999) Pharmacological characterization of the bradykinin B2 receptor: inter-species variability and dissociation between binding and functional responses. Br J Pharmacol 126: 1083-90 [PMID:10204994]

Thornton E et al. (2010) Kinin receptor antagonists as potential neuroprotective agents in central nervous system injury. Molecules 15: 6598-618 [PMID:20877247]

Whalley ET et al. (2012) Discovery and therapeutic potential of kinin receptor antagonists. Expert Opin Drug Discov 7: 1129-48 [PMID:23095011]

Nomenclature B1 receptor B2 receptor
HGNC, UniProt BDKRB1, P46663 BDKRB2, P30411
Potency order of endogenous ligands [des-Arg10]kallidin (KNG1, P01042) > [des-Arg9]bradykinin (KNG1, P01042) = kallidin (KNG1, P01042) > bradykinin (KNG1, P01042) kallidin (KNG1, P01042) > bradykinin (KNG1, P01042) ≫ [des-Arg9]bradykinin (KNG1, P01042), [des-Arg10]kallidin (KNG1, P01042)
Endogenous agonists [des-Arg10]kallidin (KNG1, P01042) [86, 129, 765, 1087] bradykinin (KNG1, P01042) [63, 924]
Selective agonists NG29 [2071], [Sar, D-Phe8,des-Arg9]bradykinin [81, 1087] NG291 [2072], labradimil [2072], [Hyp3,Tyr(Me)8]BK, [Phe8,ψ(CH2-NH)Arg9]BK
Selective antagonists B-9958 (pKi 9.2–10.3) [737, 1963], [Leu9,des-Arg10]kallidin (pKi 9.1–9.3) [86, 129], SSR240612 (pKi 9.1–9.2) [785], R-954 (pA2 8.6) [766], R-715 (pA2 8.5) [764] icatibant (pKi 10.2) [46], FR173657 (pA2 8.2) [1997], anatibant (pKi 8.2) [1913]
Labelled ligands [125I]Hpp-desArg10HOE140 (Antagonist) (pKd 10), [3H]Lys-[des-Arg9]BK (Agonist), [3H]Lys-[Leu8][des-Arg9]BK (Antagonist) [3H]BK (human, mouse, rat) (Agonist) [2553] – Mouse, [3H]NPC17731 (Antagonist) (pKd 9.1–9.4) [2667, 2668], [125I]HPP-HOE140 (Antagonist) [503, 1789], [125I][Tyr8]bradykinin (Agonist) [1432]

Calcitonin receptors

Overview

This receptor family comprises a group of receptors for the calcitonin/CGRP family of peptides. The calcitonin (CT), amylin (AMY), calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CGRP, AM, AMY, and CT receptors [891, 893, 1901]) are generated by the genes CALCR (which codes for the CT receptor) and CALCRL(which codes for the calcitonin receptor-like receptor, CLR, previously known as CRLR). Their function and pharmacology are altered in the presence of RAMPs (receptor activity-modifying proteins), which are single TM domain proteins of ca. 150 amino acids, identified as a family of three members; RAMP1, RAMP2 and RAMP3. There are splice variants of the CT receptor; these in turn produce variants of the AMY receptor [1901], some of which can be potently activated by CGRP. The endogenous agonists are the peptides calcitonin (CALCA, P01258), α-CGRP (CALCA, P06881) (formerly known as CGRP-I), β-CGRP (CALCB, P10092) (formerly known as CGRP-II), amylin (IAPP, P10997) (occasionally called islet-amyloid polypeptide, diabetes-associated polypeptide), adrenomedullin (ADM, P35318) and adrenomedullin 2/intermedin (ADM2, Q7Z4H4). There are species differences in peptide sequences, particularly for the CTs. CTR-stimulating peptide {Pig} (CRSP) is another member of the family with selectivity for the CT receptor but it is not expressed in humans [1125]. CLR (calcitonin receptor-like receptor) by itself binds no known endogenous ligand, but in the presence of RAMPs it gives receptors for CGRP, adrenomedullin and adrenomedullin 2/intermedin. There are several approved drugs that target this receptor family, such as pramlintide, erenumab, and the"gepant" class of CGRP receptor antagonists.

Further reading on Calcitonin receptors

Hay DL et al. (2018) Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25. Br J Pharmacol 175: 3-17 [PMID:29059473]

Hay DL et al. (2016) Receptor Activity-Modifying Proteins (RAMPs): New Insights and Roles. Annu Rev Pharmacol Toxicol 56: 469-87 [PMID:26514202]

Kato J et al. (2015) Bench-to-bedside pharmacology of adrenomedullin. Eur J Pharmacol 764: 140-8 [PMID:26144371]

Russell FA et al. (2014) Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev 94: 1099-142 [PMID:25287861]

Russo AF. (2015) Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev Pharmacol Toxicol 55: 533-52 [PMID:25340934]

Nomenclature CT receptor AMY1 receptor AMY2 receptor AMY3 receptor
HGNC, UniProt CALCR, P30988
Subunits CT receptor, RAMP1 (Accessory protein) CT receptor, RAMP2 (Accessory protein) CT receptor, RAMP3 (Accessory protein)
Potency order of endogenous ligands calcitonin (salmon)calcitonin (CALCA, P01258) ≥ amylin (IAPP, P10997), α-CGRP (CALCA, P06881), β-CGRP (CALCB, P10092) > adrenomedullin (ADM, P35318), adrenomedullin 2/intermedin (ADM2, Q7Z4H4) calcitonin (salmon)amylin (IAPP, P10997) ≥ α-CGRP (CALCA, P06881), β-CGRP (CALCB, P10092) > adrenomedullin 2/intermedin (ADM2, Q7Z4H4) ≥ calcitonin (CALCA, P01258) > adrenomedullin (ADM, P35318) Poorly defined calcitonin (salmon)amylin (IAPP, P10997) > α-CGRP (CALCA, P06881), β-CGRP (CALCB, P10092) ≥ adrenomedullin 2/intermedin (ADM2, Q7Z4H4) ≥ calcitonin (CALCA, P01258) > adrenomedullin (ADM, P35318)
Endogenous agonists calcitonin (CALCA, P01258) [38, 71, 889, 1278, 1364, 1661] α-CGRP (CALCA, P06881) [889, 1277, 1278, 1364, 2469], amylin (IAPP, P10997) [756], β-CGRP (CALCB, P10092) amylin (IAPP, P10997) [756] amylin (IAPP, P10997) [756]
Agonists pramlintide [756] pramlintide [756] pramlintide [756]
Antagonists CT-(8-32) (salmon) (pKd 9) [939], AC187 (pKi 7.2) [889] AC187 (pKi 8) [889], CT-(8-32) (salmon) (pKi 7.8) [889], olcegepant (pKd 7.2) [2469] CT-(8-32) (salmon) (pKi 7.9) [889], AC187 (pKi 7.7) [889]
Labelled ligands [125I]CT (human) (Agonist), [125I]CT (salmon) (Agonist) [125I]αCGRP (human) (Agonist), [125I]BH-AMY (rat, mouse) (Agonist) [125I]BH-AMY (rat, mouse) (Agonist) [125I]BH-AMY (rat, mouse) (Agonist)

Nomenclature calcitonin receptor-like receptor CGRP receptor AM1 receptor AM2 receptor
HGNC, UniProt CALCRL, Q16602
Subunits calcitonin receptor-like receptor, RAMP1 (Accessory protein) calcitonin receptor-like receptor, RAMP2 (Accessory protein) calcitonin receptor-like receptor, RAMP3 (Accessory protein)
Potency order of endogenous ligands α-CGRP (CALCA, P06881), β-CGRP (CALCB, P10092) > adrenomedullin (ADM, P35318) ≥ adrenomedullin 2/intermedin (ADM2, Q7Z4H4) > amylin (IAPP, P10997) ≥ calcitonin (salmon) adrenomedullin (ADM, P35318) > adrenomedullin 2/intermedin (ADM2, Q7Z4H4) > α-CGRP (CALCA, P06881), β-CGRP (CALCB, P10092), amylin (IAPP, P10997) > calcitonin (salmon) adrenomedullin (ADM, P35318) ≥ adrenomedullin 2/intermedin (ADM2, Q7Z4H4) ≥ α-CGRP (CALCA, P06881), β-CGRP (CALCB, P10092) > amylin (IAPP, P10997) > calcitonin (salmon)
Endogenous agonists β-CGRP (CALCB, P10092) [27, 1555], α-CGRP (CALCA, P06881) [27, 1555] adrenomedullin (ADM, P35318) [27, 1555] adrenomedullin (ADM, P35318) [27, 664]
Antagonists olcegepant (pKi 10.7–11) [551, 890, 892, 1097, 1491], telcagepant (pKi 9.1) [2048] AM-(22-52) (human) (pKi 7–7.8) [892] AM-(22-52) (human)
Labelled ligands [125I]αCGRP (human) (Agonist), [125I]αCGRP (mouse, rat) (Agonist) [125I]AM (rat) (Agonist) [125I]AM (rat) (Agonist)

Comments

It is important to note that a complication with the interpretation of pharmacological studies with AMY receptors in transfected cells is that most of this work has likely used a mixed population of receptors, encompassing RAMP-coupled CTR as well as CTR alone. This means that although in binding assays human calcitonin (CALCA, P01258) has low affinity for 125I-AMY binding sites, cells transfected with CTR and RAMPs can display potent CT functional responses. Transfection of human CTR with any RAMP can generate receptors with a high affinity for both salmon CT and AMY and varying affinity for different antagonists [412, 889, 890]. The major human CTR splice variant(hCT(a), which does not contain an insert) with RAMP1 (i.e. the AMY1(a) receptor) has a high affinity for CGRP [2469], unlike hCT(a)-RAMP3(i.e. AMY3(a) receptor) [412, 889]. However, the AMY receptor phenotype is RAMP-type, splice variant and cell-line-dependent [1638, 1919, 2355]. Emerging data suggests that AMY1 could be a second CGRP receptor [888]. There are also species differences in agonist pharmacology.

The ligands described have limited selectivity. Adrenomedullin has appreciable affinity for CGRP receptors. CGRP can show significant cross-reactivity at AMY receptors and AM2 receptors. Adrenomedullin 2/intermedin also has high affinity for the AM2 receptor [969]. CGRP-(8-37) acts as an antagonist of CGRP(pKi˜8) and inhibits some AM and AMY responses (pKi ˜6-7). It is weak at CT receptors. Human AM-(22-52) has some selectivity towards AM receptors, but with modest potency (pKi ˜7), limiting its use [892]. Olcegepant (also known as BIBN4096BS, pKi˜10.5) and telcagepant (also known as MK0974, pKi˜9) are examples of the "gepant" class of small molecule antagonists. These are selective for the CGRP receptor over the AM receptors but depending on the compound, have variable affinity for the AMY1 receptor. These antagonists tend to have higher affinity at primate receptors, compared to rodent receptors [1630, 2469].

Gs is a prominent route for effector coupling for CLR and CTR but other pathways (e.g. Ca2+, ERK, Akt), and G proteins can be activated [2468]. There is evidence that CGRP-RCP (a 148 amino-acid hydrophilic protein, ASL (P04424) is important for the coupling of CLR to adenylyl cyclase [617].

[125I]-Salmon CT is the most common radioligand for CT receptors but it has high affinity for AMY receptors and is also poorly reversible.

Calcium-sensing receptor

Overview

The calcium-sensing receptor (CaS, provisional nomenclature as recommended by NC-IUPHAR [652] and subsequently updated [1323]) responds to multiple endogenous ligands, including extracellular calcium and other divalent/trivalent cations, polyamines and polycationic peptides, L-amino acids (particularly L-Trp and L-Phe), glutathione and various peptide analogues, ionic strength and extracellular pH(reviewed in [1325]). While divalent/trivalent cations, polyamines and polycations are CaS receptor agonists [269, 1927], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [438, 652, 950, 1925, 1926]. Indeed, L-amino acids have been identified as "co-agonists", with both concomitant calcium and L-amino acid binding required for full receptor activation [730, 2657]. The sensitivity of the CaS receptor to primary agonists is increased by elevated extracellular pH [305] or decreased extracellular ionic strength [1926]. This receptor bears no sequence or structural relation to the plant calcium receptor, also called CaS.

Further reading on Calcium-sensing receptor

Brown EM. (2013) Role of the calcium-sensing receptor in extracellular calcium homeostasis. Best Pract Res Clin Endocrinol Metab 27: 333-43 [PMID:23856263]

Conigrave AD et al. (2013) Calcium-sensing receptor (CaSR): pharmacological properties and signaling pathways. Best Pract Res Clin Endocrinol Metab 27: 315-31 [PMID:23856262]

Hannan FM et al. (2018) The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases. Nat Rev Endocrinol 15: 33-51 [PMID:30443043]

Leach K et al. (2020) International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function. Pharmacol Rev 72: 558-604 [PMID:32467152]

Nemeth EF et al. (2018) Discovery and Development of Calcimimetic and Calcilytic Compounds. Prog Med Chem 57: 1-86 [PMID:29680147]

Nomenclature CaS receptor
HGNC, UniProt CASR, P41180
Amino-acid rank order of potency L-phenylalanine, L-tryptophan, L-histidine> L-alanine> L-serine, L-proline, L-glutamic acid> L-aspartic acid (not L-lysine, L-arginine, L-leucine and L-isoleucine) [438]
Cation rank order of potency Gd3+> Ca2+> Mg2+ [269]
Glutamyl peptide rank order of potency S-methylglutathione ≈γGlu-Val-Gly > glutathione >γGlu-Cys [260, 1771, 2487]
Polyamine rank order of potency spermine> spermidine> putrescine [1927]
Allosteric modulators ATF936 (Negative) (pIC50 8.9) [2537], encaleret (Negative) (pIC50 7.9) [2156], SB-423562 (Negative) (pIC50 7.1) [1271], evocalcet (Positive) (pEC50 7) [1601], ronacaleret (Negative) (pIC50 6.5–6.8) [110], NPS 2143 (Negative) (pKB 6.2–6.7) [489, 1322, 1326], cinacalcet (Positive) (pKB 5.9–6.6) [441, 489, 1322, 1326], tecalcet (Positive) (pKB 6.2–6.6) [441, 489], AC265347 (Positive) (pKB 6.3–6.4) [441, 1322], calhex 231 (Negative) (pIC50 6.4) [1863], calindol (Positive) (pKB 6.3) [441], etelcalcetide (Positive) (pEC50 4.6) [2472]

Comments

The CaS receptor has a number of physiological functions, but it is best known for its central role in parathyroid and renal regulation of extracellular calcium homeostasis [856]. This is seen most clearly in patients with loss-of-function CaS receptor mutations who develop familial hypocalciuric hypercalcaemia(heterozygous mutations) or neonatal severe hyperparathyroidism (heterozygous, compound heterozygous or homozygous mutations) [856] and in Casr null mice [354, 950], which exhibit similar increases in PTH secretion and blood calcium levels. Gain-of-function CaS mutations are associated with autosomal dominant hypocalcaemia and Bartter syndrome type V [856].

The CaS receptor primarily couples to Gq/11, G12/13 and Gi/o [489, 741, 992, 2345], but in some cell types can couple to Gs [1493]. However, the CaS receptor can form heteromers with Class C GABAB [355, 382] and mGlu1/5 receptors [697], which may introduce further complexity in its signalling capabilities.

Multiple other small molecule chemotypes are positive and negative allosteric modulators of the CaS receptor [1159, 1713]. Further, etelcalcetide is a novel peptide positive allosteric modulator of the receptor, that also displays weak agonist activity [2472]. Agonists and positive allosteric modulators of the CaS receptor are termed Type I and II calcimimetics, respectively, and can suppress parathyroid hormone (PTH (PTH, P01270)) secretion [1715]. Negative allosteric modulators are called calcilytics and can act to increase PTH (PTH, P01270) secretion  [1714].

Where functional pKB values are provided for allosteric modulators,