THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Introduction and Other Protein Targets

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.15537. 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‐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.


Table of contents S1 Introduction and Other Protein Targets
S8 Adiponectin receptors S9 Aryl hydrocarbon receptor S10 Non-enzymatic BRD containing proteins S11 CD molecules S13 Methyllysine reader proteins S14 Fatty acid-binding proteins S16 Notch receptors S17 Regulators of G protein Signaling (RGS) proteins S17 RZ family S18 R4 family S19 R7 family S19 R12  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 Searchable database: http://www.guidetopharmacology.org/index.jsp Overview S2 Full Contents of ConciseGuide: http://onlinelibrary.wiley.com/doi/10.1111/bph.15537/full 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 S157 Ion channels S159 Ligand-gated ion channels S160 5-HT 3 receptors S162 Acid-sensing (proton-gated) ion channels (ASICs) S165 Epithelial sodium channel (ENaC) S166 GABA A receptors S172 Glycine receptors S175 Ionotropic glutamate receptors S180 IP 3 receptors S181 Nicotinic acetylcholine receptors S185 P2X receptors S187 ZAC S188 Voltage-gated ion channels S188 CatSper and Two-Pore channels S190 Cyclic nucleotide-regulated channels S192 Potassium channels S193 Calcium-and sodium-activated potassium channels S195 Inwardly rectifying potassium channels S199 Two-pore domain potassium channels S201 Voltage-gated potassium channels S204 Ryanodine receptors S205 Transient Receptor Potential channels S219 Voltage-gated calcium channels S222 Voltage-gated proton channel S223 Voltage-gated sodium channels S225 Aquaporins S227 Chloride channels S228 ClC family S230 CFTR S231 Calcium activated chloride channel S232 Maxi chloride channel , 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 at-tempts to fit in within the general guidelines from NC-IUPHAR. This current edition, the Concise Guide to PHARMACOLOGY 2021/22, is the latest snapshot of the database in print form, following on from the Concise Guide to PHARMACOLOGY 2019/20. 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 sup-porting 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. (2021). The Concise Guide to PHARMACOL-OGY 2021/22: Overview. Br J Pharmacol 178: S1-S26. In this overview are listed protein targets of pharmacological interest, which are not G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, transporters or enzymes. For obvious reasons, we have included potential drug targets of the SARS-CoV-2 virus, despite the current limited pharmacological data.
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 [121]. Comments: T-Cadherin (CDH13, P55290) has also been suggested to be a receptor for (hexameric) adiponectin [47].

Aryl hydrocarbon receptor
Other protein targets → Aryl hydrocarbon receptor Overview: The aryl hydrocarbon receptor, highly expressed in the liver and barrier organs, is resident in the cytoplasm bound to the chaperone heat shock protein hsp90. Upon agonist activation, the ligand:aryl hydrocarbon receptor complex migrates to the nucleus and binds the aryl hydrocarbon receptor nuclear translocator (ARNT, P27540, also known as HIF1β). The complex regulates transcription of selected genes through interaction with xenobiotic response elements (XRE). Among the genes regulated by the AHR/ARNT complex are cytochrome P450s, particularly CYP1A1, and the period circadian protein homolog 1 (PER1, O15534). The aryl hydrocarbon receptor is also capable of non-genomic signalling.

Non-enzymatic BRD containing proteins
Other protein targets → Bromodomain-containing proteins → Non-enzymatic BRD containing proteins Overview: Bromodomains bind proteins with acetylated lysine residues, such as histones, to regulate gene transcription. Listed herein are examples of bromodomain-containing proteins for which sufficient pharmacology exists.

CD molecules
Other protein targets → CD molecules Overview: Cluster of differentiation refers to an attempt to catalogue systematically a series of over 300 cell-surface proteins associated with immunotyping. Many members of the group have identified functions as enzymes (for example, see CD73 ecto-5'-nucleotidase) or receptors (for example, see CD41 integrin, alpha 2b subunit). Many CDs are targeted for therapeutic gain using antibodies for the treatment of proliferative disorders. A full listing of all the Clusters of Differentiation proteins is not possible in the Guide to PHARMACOLOGY; listed herein are selected members of the family targeted for therapeutic gain.

Further reading on CD molecules
Bewersdorf JP et al.

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 [99]) or for interaction with metabolic enzymes. Although sequence homology is limited, crystallographic studies suggest conserved 3D structures across the group of binding proteins.  Comments Able to transport bile acids [142]. Crystal structure of the human FABP7 [9].

Notch receptors
Other protein targets → Notch receptors Overview: Aberrant Notch signalling is implicated in a number of human cancers [59,80,108,126], and there is intense pharmaceutical activity being directed towards achieving clinically effective Notch pathway inhibition [24,75].  -Comments Various types of activating and inactivating NOTCH1 mutations have been reported to be associated with human diseases, for example: aortic valve disease [29,73], Adams-Oliver syndrome 5 [114], T-cell acute lymphoblastic leukemia (T-ALL) [130], chronic lymphocytic leukemia (CLL) [89] and head and neck squamous cell carcinoma [1,115].

Further reading on Notch receptors
--Notch receptor 4 is a potential therapeutic molecular target for triple-negative breast cancer [60,77].

Other protein targets → Regulators of G protein Signaling (RGS) proteins
Overview: Regulator of G protein Signaling, or RGS, proteins serve an important regulatory role in signaling mediated by G protein-coupled receptors (GPCRs). They all share a common RGS domain that directly interacts with active, GTP-bound Gα subunits of heterotrimeric G proteins. RGS proteins stabilize the transition state for GTP hydrolysis on Gα and thus induce a conformational change in the Gα subunit that accelerates GTP hydrolysis, thereby effectively turning off signaling cascades mediated by GPCRs. This GTPase accelerating protein (GAP) activity is the canonical mechanism of action for RGS proteins, although many also possess additional functions and domains. RGS proteins are divided into four families, R4, R7, R12 and RZ based on sequence homology, domain structure as well as specificity towards Gα subunits. For reviews on RGS proteins and their potential as therapeutic targets, see e.g. [5,45,79,93,105,106,107,138,140].

RZ family
Other protein targets → Regulators of G protein Signaling (RGS) proteins → RZ family Overview: The RZ family of RGS proteins is less well characterized than the other families. It consists of, RGS17 (also known as RGSZ2), RGS19 (also known as GAIP) and RGS20 (with several splice variants including RGSZ1 and Ret-RGS). All members contain an N-terminal cysteine string motif [62] which is a site of palmitoylation and could serve functions in membrane targeting, protein stability or aid protein-protein interactions [2,62]. However, the function in the case of RZ family RGS proteins is not yet fully understood. Members of the RZ family of RGS proteins are the only RGS proteins that have selective GAP activity for Gα z , a function that resulted in the name of the family [31,71,127,134]. However, the members of the RZ family are able to also GAP Gα i/o members with varying selectivity.

R4 family
Other protein targets → Regulators of G protein Signaling (RGS) proteins → R4 family Overview: The R4 family of RGS proteins is the largest family of RGS proteins with 10 members. Each of the R4 family members contain only small N-and C-termini apart from the RGS domain. The N-terminal amphipathic helix present in most R4 family members serves an important function in membrane association and can directly bind phospholipids. In contrast to the RGS domain, which is well conserved among members of the R4 family of RGS proteins, the N-and C-termini vary, enabling specificity of non-GAP functions. Despite the non-complex structure of these proteins, several R4 family RGS proteins have been shown to possess additional functions apart from acting as GAPs at activated Gα subunits [11,96].

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 [98] 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.

Further reading on Sigma receptors
Chu UB et al.  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 [84].
These amyloidogenic mutants are linked to the development of pathological amyloidoses, including familial amyloid polyneuropathy (FAP) [7,20], familial amyloid cardiomyopathy (FAC) [49], amyloidotic vitreous opacities, carpal tunnel syndrome [76] and others. In old age, non-mutated TTR can also form pathological amyloid fibrils [131]. Pharmacological intervention to reduce or prevent TTR dissociation is being pursued as a therapeutic 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. Comments: Excess production and accumulation of TTR causes hereditary transthyretin-mediated amyloidosis. Two novel drugs are now approved to combat this disease: inotersen (Tegsedi ® ) [52] and patisiran (Onpattro ® ) [46]. Both of these drugs act to reduce the amount of TTR protein (both wild type and mutant) produced in the liver, but by slightly different mechanisms. Inotersen is an antisense oligonucleotide inhibitor of TTR synthesis, whereas patisiran is a double-stranded small interfering RNA (which targets a conserved sequence in the 3' UTR of mutant and wild-type TTR mRNA). Inotersen is administered subcutaneously, and patisiran is delivered by intravenous infusion in a lipid nanoparticle formulation. 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.

Structural proteins
Other protein targets → SARS-CoV-2 → Structural proteins Overview: The virus particle has four structural proteins. The envelope, membrane and spike proteins are on the viral surface, while the polybasic nucleoprotein enables the tight coiling of the viral RNA.

Nomenclature
Envelope The coronavirus nucleocapsid phosphoprotein (N, or nucleoprotein) is highly basic and binds the viral RNA as a dimeric entity [25] into nucleocapsids which protect the viral genome, while also providing access for replication when required The spike protein extends from the viral surface and binds to the host cell surface enzyme ACE2 to facilitate viral entry into the cell The 3C-like protease cleaves the two polyproteins encoded by the SARS-CoV-2 genome (pp1a and pp1ab) into a range of non-structural proteins (nsp1-11 from pp1a; nsp1-16 from pp1ab). As these component proteins play crucial roles in viral replication, the 3C-like protease is considered to be a good molecular target for drug development. Small molecule 3C-like protease inhibitors would be predicted to reduce viral replication [33,85] The papain-like protease is a domain within coronavirus Nsp3. Its proteolytic activity cleaves three sites in the viral replicase polyprotein (recognition consensus sequence LXGG↓XX) to release the three non-structural proteins Nsp1, Nsp2, and Nsp3 [40]. It has additional non-proteolytic functions as part of the multicomponent replicase-transcriptase complex [103]  [48,122]. This complex may participate in viral replication by acting as a primase for de novo initiation of RNA synthesis The conservation of RdRP catalytic domain between different RNA viruses endows inhibitors that were designed against other viral pathogens with activity against the SARS coronaviruses. Viral RdRP is the molecular target of nucleotide-based broad-spectrum antiviral compounds like remdesivir, tenofovir and ribavirin [33,129,141] Other proteins The main function of the SARS-CoV protein 7a appears to be disruption of the host cell cycle and induction of caspase-dependent apoptosis [120]. By homology SARS-CoV-2 protein 7a is likely to produce the same effect SARS-CoV protein 9b is a virion-associated accessory protein [120] that acts to block the host's ability to mount an antiviral IFN-induced innate immune response [87]. By homology, 9b from SARS-CoV-2 would be predicted to exhibit a similar function Coronavirus nsp6 proteins limit autophagosome expansion [21]. This mechanism may favour coronavirus infection by damaging autophagosome-mediated delivery of viral components to lysosomes for degradation Protein 7b is a coronavirus accessory protein. Experimental evidence suggests that SARS-CoV 7b has some attenuating function [87]. By homology, SARS-CoV-2 7b is likely to have a similar function