THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Overview

The Concise Guide to PHARMACOLOGY 2017/18 is the third in this series of biennial publications. This version provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to an open access knowledgebase of drug targets and their ligands (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.13882/full. In addition to this overview, in which are identified ‘Other protein targets’ which fall outside of the subsequent categorisation, there are eight areas of focus: G protein‐coupled receptors, ligand‐gated ion channels, voltage‐gated ion channels, other 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‐2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.


Abstract
The Concise Guide to PHARMACOLOGY 2017/18 is the third in this series of biennial publications. This version provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to an open access knowledgebase of drug targets and their ligands (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.13882/full. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are eight areas of focus: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other 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-2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
Table of contents S1 Overview S6 Other Protein Targets S6 Adiponectin receptors S7 Blood coagulation components S8 Non-enzymatic BRD containing proteins S8 Carrier proteins S9 CD molecules S10 Methyllysine reader proteins S11 Fatty acid-binding proteins S13 Notch receptors S13 Regulators of G protein Signaling (RGS) proteins S14 Sigma receptors S15 Tubulins S17 G protein-coupled receptors S19 Orphan and other 7TM receptors S19 Class A Orphans S28 Class C Orphans S28 Taste  S101 Parathyroid hormone receptors S101 Platelet-activating factor receptor S102 Prokineticin receptors S103 Prolactin-releasing peptide receptor S104 Prostanoid receptors S106 Proteinase-activated receptors S107 QRFP receptor S108 Relaxin family peptide receptors S110 Somatostatin receptors S111 Succinate receptor S111 Tachykinin receptors S113 Thyrotropin-releasing hormone receptors S113 Trace amine receptor S114 Urotensin receptor S115 Vasopressin and oxytocin receptors S117 VIP and PACAP receptors S130 Ligand-gated ion channels S131 5-HT 3 receptors S133 Acid-sensing (proton-gated) ion channels (ASICs) S135 Epithelial sodium channels (ENaC) S137 GABA A receptors S142 Glycine receptors S145 Ionotropic glutamate receptors S150 IP 3 receptor S151 Nicotinic acetylcholine receptors S154 P2X receptors S156 ZAC S160 Voltage-gated ion channels S161 CatSper and Two-Pore channels S163 Cyclic nucleotide-regulated channels S164 Potassium channels S165 Calcium-and sodium-activated potassium channels S166 Inwardly rectifying potassium channels S169 Two P domain potassium channels S171 Voltage-gated potassium channels S175 Ryanodine receptor S176 Transient Receptor Potential channels S186 Voltage-gated calcium channels S189 Voltage-gated proton channel S190 Voltage-gated sodium channels S195 Other ion channels S196 Aquaporins S197 Chloride channels S197 ClC family S199 CFTR S200 Calcium activated chloride channel S201 Maxi chloride channel S202 Volume regulated chloride channels S204 Connexins and Pannexins S206 Sodium leak channel, non-selective In order to allow clarity and consistency in pharmacology, there is a need for a comprehensive organisation and presentation of the targets of drugs. This is the philosophy of the IUPHAR/BPS Guide to PHARMACOLOGY presented on the online free access database (http://www.guidetopharmacology.org/). This database is supported by the British Pharmacological Society (BPS), the International Union of Basic and Clinical Pharmacology (IUPHAR), the University of Edinburgh and previously the Wellcome Trust. Data included in the Guide to PHARMACOLOGY are derived in large part from interactions with the subcommittees of the Nomenclature Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR). A major influence on the development of the database was Tony Harmar (1951-2014), 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 2017/18, is the latest snapshot of the database in print form, following on from the Concise Guide to PHARMACOLOGY 2015/16. 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. 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 nine sections, which comprise pharmacological targets of similar structure/function. These are G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, 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. (2017). The Concise Guide to PHARMACOL-OGY 2017/18: Overview. Br J Pharmacol 174: S1-S16.
In this overview are listed protein targets of pharmacological interest, which are not G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, ion channels, nuclear hormone receptors, catalytic receptors, transporters or enzymes.

Other Protein Targets
Family structure

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 [49]. 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 [90]. 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 [93].

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.

Fatty acid-binding proteins
Other protein targets → Fatty acid-binding proteins Overview: Fatty acid-binding proteins are low molecular weight (100-130 aa) chaperones for long chain fatty acids, fatty acyl CoA esters, eicosanoids, retinols, retinoic acids and related metabolites and are usually regarded as being responsible for allowing the otherwise hydrophobic ligands to be mobile in aqueous media. These binding proteins may perform functions extracellularly (e.g. in plasma) or transport these agents; to the nucleus to interact with nuclear receptors (principally PPARs and retinoic acid receptors [70]) or for interaction with metabolic enzymes. Although sequence homology is limited, crystallographic studies suggest conserved 3D structures across the group of binding proteins.  [46] Comments A broader substrate specificity than other FABPs, binding two fatty acids per protein [82].
Crystal structure of the human FABP7 [5].
In silico modelling suggests that PMP2/FABP8 can bind both fatty acids and cholesterol [50].

Notch receptors
Other protein targets → Notch receptors Overview: The canonocal 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 [2]. 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 [18,57,71,89]. This is why γ-secretase inhibitors can be used to downregulate Notch signalling and explains their anti-cancer action. One such small molecule is RO4929097 [47], although development of this compound has been terminated following an unsuccessful Phase II single agent clinical trial in metastatic colorectal cancer [78].

Further reading on Notch receptors
Borggrefe T et al.

Regulators of G protein Signaling (RGS) proteins
Other protein targets → Regulators of G protein Signaling (RGS) proteins Overview: Regulators of G protein signalling (RGS) proteins increase the deactivation rates of G protein signalling pathways through enhancing the GTPase activity of the G protein alpha subunit. Interactions through protein:protein interactions of many RGS proteins have been identified for targets other than heteromeric G proteins. The 20 RGS proteins are commonly divided into four families (R4, R7, R12 and RZ) based on sequence and domain homology. Described here is RGS4 for which a number of pharmacological inhibitors have been described.

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 [94] 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.