THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Introduction and Other Protein Targets

The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 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 (http://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 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/10.1111/bph.14747. In addition to this overview, in which are identified Other protein targets which fall outside of the subsequent categorisation, there are six areas of focus: G protein‐coupled receptors, 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‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

contents S1 Introduction and Other Protein Targets S6 Adiponectin receptors S7 Blood coagulation components S8 Non-enzymatic BRD containing proteins S9 Carrier proteins S9 CD molecules S11 Methyllysine reader proteins S11 Fatty acid-binding proteins S14 Notch receptors S15 Regulators of G protein Signaling (RGS) proteins S18 Sigma receptors S19 Tubulins Neuropeptide FF/neuropeptide AF receptors S100 Neuropeptide S receptor S101 Neuropeptide W/neuropeptide B receptors S102 Neuropeptide Y receptors S103 Neurotensin receptors S104 Opioid receptors S106 Orexin receptors S107 Oxoglutarate receptor S108 P2Y receptors S110 Parathyroid hormone receptors S111 Platelet-activating factor receptor S112 Prokineticin receptors S113 Prolactin-releasing peptide receptor S114 Prostanoid receptors S116 Proteinase-activated receptors S117 QRFP receptor S118 Relaxin family peptide receptors S120 Somatostatin receptors S121 Succinate receptor S122 Tachykinin receptors S123 Thyrotropin-releasing hormone receptors S124 Trace amine receptor S125 Urotensin receptor S126 Vasopressin and oxytocin receptors S127 VIP and PACAP receptors S142 Ion channels S143 Ligand-gated ion channels S144 5-HT receptors 3 S146 Acid-sensing (proton-gated) ion channels (ASICs) S148 Epithelial sodium channel (ENaC) S149 GABA receptors A S155 Glycine receptors S158 Ionotropic glutamate receptors S164 IP receptor 3 S165 Nicotinic acetylcholine receptors S168 P2X receptors S170 ZAC S171 Voltage-gated ion channels S171 CatSper and Two-Pore channels S173 Cyclic nucleotide-regulated channels S175 Potassium channels S175 Calcium-and sodium-activated potassium channels S178 Inwardly rectifying potassium channels S182 Two P domain potassium channels S185 Voltage-gated potassium channels S189 Ryanodine receptors S190 Transient Receptor Potential channels S204 Voltage-gated calcium channels S207 Voltage-gated proton channel S208 Voltage-gated sodium channels  , who worked with a passion to establish the curators as a team of highly informed and informative individuals, with a focus on high-quality data input, ensuring a suitably validated dataset. The Editors of the Concise Guide have compiled the individual records, in concert with the team of Curators, drawing on the expert knowledge of these latter subcommittees. The tables allow an indication of the status of the nomenclature for the group of targets listed, usually previously published in Pharmacological Reviews. In the absence of an established subcommittee, advice from several prominent, independent experts has generally been obtained to produce an authoritative consensus on nomenclature, which attempts to fit in within the general guidelines from NC-IUPHAR. This current edition, the Concise Guide to PHARMACOLOGY 2019/20, is the latest snapshot of the database in print form, following on from the Concise Guide to PHARMACOLOGY 2017/18. It contains data drawn from the online database as a rapid overview of the major pharmacological targets. Thus, there are many fewer targets presented in the Concise Guide compared to the online database. The priority for inclusion in the Concise Guide is the presence of quantitative pharmacological data for human proteins. This means that often orphan family members are not presented in the Concise Guide, although structural information is available on the online database. The organisation of the data is tabular (where appropriate) with a standardised format, where possible on a single page, intended to aid understanding of, and comparison within, a particular target group. The Concise Guide is intended as an initial resource, with links to additional reviews and resources for greater depth and information. Pharmacological and structural data focus primarily on human gene products, wherever possible, with links to HGNC gene nomenclature and UniProt IDs. In a few cases, where data from human proteins are limited, data from other species are indicated. Pharmacological tools listed are prioritised on the basis of selectivity and availability. That is, agents (agonists, antagonists, inhibitors, activators, etc.) are included where they are both available (by donation or from commercial sources, now or in the near future) AND the most selective. The Concise Guide is divided into seven sections, which comprise pharmacological targets of similar structure/function. These are G protein-coupled receptors, ion channels (combining previous records of ligand-gated, voltage-gated and other ion channels), catalytic receptors, nuclear hormone receptors, enzymes, transporters and other protein targets. We hope that the Concise Guide will provide for researchers, teachers and students a state-of-the art source of accurate, curated information on the background to their work that they will use in the Introductions to their Research Papers or Reviews, or in supporting their teaching and studies. We recommend that any citations to information in the Concise Guide are presented in the following format: Alexander SPH et al. (

Adiponectin receptors
Other protein targets → Adiponectin receptors

Overview:
Adiponectin receptors (provisional nomenclature, ENSFM00500000270960) respond to the 30 kDa complement-related protein hormone adiponectin (also known as ADIPOQ: adipocyte, C1q and collagen domain-containing protein; ACRP30, adipose most abundant gene transcript 1; apM-1; gelatin-binding protein: Q15848) originally cloned from adipocytes [57]. Although sequence data suggest 7TM domains, immunological evidence indicates that, contrary to typical 7TM topology, the carboxyl terminus is extracellular, while the amino terminus is intracellular [111]. Signalling through these receptors appears to avoid G proteins; modelling based on the crystal structures of the adiponectin receptors suggested ceramidase acivity, which would make these the first in a new family of catalytic receptors [98]. Introduction Comments: T-Cadherin (CDH13, P55290) has also been suggested to be a receptor for (hexameric) adiponectin [36].

Blood coagulation components
Other protein targets → Blood coagulation components Overview: Coagulation as a process is interpreted as a mechanism for reducing excessive blood loss through the generation of a gel-like clot local to the site of injury. The process involves the activation, adhesion (see Integrins), degranulation and aggregation of platelets, as well as proteins circulating in the plasma. The coagulation cascade involves multiple proteins being converted to more active forms from less active precursors, typically through proteolysis (see Proteases). Listed here are the components of the coagulation cascade targetted by agents in current clinical usage.

Carrier proteins
Other protein targets → Carrier proteins Overview: Transthyretin (TTR) is a homo-tetrameric protein which transports thyroxine in the plasma and cerebrospinal fluid and retinol (vitamin A) in the plasma. Many disease causing mutations in the protein have been reported, many of which cause complex dissociation and protein mis-assembly and deposition of toxic aggregates amyloid fibril formation [73]. These amyloido-genic mutants are linked to the development of pathological amyloidoses, including familial amyloid polyneuropathy (FAP) [6,16], familial amyloid cardiomyopathy (FAC) [37], amyloidotic vitreous opacities, carpal tunnel syndrome [63] and others. In old age, non-mutated TTR can also form pathological amyloid fibrils [108]. Pharmacological intervention to reduce or prevent TTR dis-sociation is being pursued as a theapeutic strategy. To date one small molecule kinetic stabilising molecule (tafamidis) has been approved for FAP, and is being evaluated in clinical trials for other TTR amyloidoses.

CD molecules
Other protein targets → CD molecules

Notch receptors
Other protein targets → Notch receptors Overview: The canonical Notch signalling pathway has four type I transmembrane Notch receptors (Notch1-4) and five ligands (DLL1, 2 and 3, and Jagged 1-2). Each member of this highly conserved receptor family plays a unique role in cell-fate determination during embryogenesis, differentiation, tissue patterning, proliferation and cell death [3]. As the Notch ligands are also membrane bound, cells have to be in close proximity for receptor-ligand interactions to occur. Cleavage of the intracellular domain (ICD) of activated Notch receptors by γ-secretase is required for downstream signalling and Notch-induced transcriptional modulation [20,66,83,109]. This is why γ-secretase inhibitors can be used to downregulate Notch signalling and explains their anticancer action. One such small molecule is RO4929097 [54], although development of this compound has been terminated following an unsuccessful Phase II single agent clinical trial in metastatic colorectal cancer [94].

Sigma receptors
Other protein targets → Sigma receptors Overview: Although termed 'receptors', the evidence for coupling through conventional signalling pathways is lacking. Initially described as a subtype of opioid receptors, there is only a modest pharmacological overlap and no structural convergence with the G protein-coupled receptors; the crystal structure of the sigma1 receptor [81] suggests a trimeric structure of a single short transmembrane domain traversing the endoplasmic reticulum membrane, with the bulk of the protein facing the cytosol. A wide range of compounds, ranging from psychoactive agents to antihistamines, have been observed to bind to these sites.

Tubulins
Other protein targets → Tubulins Overview: Tubulins are a family of intracellular proteins most commonly associated with microtubules, part of the cytoskeleton. They are exploited for therapeutic gain in cancer chemotherapy as targets for agents derived from a variety of natural products: taxanes, colchicine and vinca alkaloids. These are thought to act primarily through β-tubulin, thereby interfering with the normal processes of tubulin polymer formation and disassembly. --