S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, 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. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: 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 Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates. Conflict of interest The authors state that there are no conflicts of interest to declare. ­c 2015 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Overview: G protein-coupled receptors (GPCRs) are the largest loops (ICL1-ICL3). About 800 GPCRs have been identified in vided them, on the basic of sequence homology, into six classes. class of membrane proteins in the human genome. The term man, of which about half have sensory functions, mediating ol- These classes and their prototype members were as follows: Class "7TM receptor" is commonly used interchangeably with "GPCR", faction ( 400), taste (33), light perception (10) and pheromone A (rhodopsin-like), Class B (secretin receptor family), Class C although there are some receptors with seven transmembrane signalling (5) [1309]. The remaining 350 non-sensory GPCRs (metabotropic glutamate), Class D (fungal mating pheromone domains that do not signal through G proteins. GPCRs share mediate intersignalling by ligands that range in size from small receptors), Class E (cyclic AMP receptors) and Class F (friz- a common architecture, each consisting of a single polypeptide molecules to peptide to large proteins; they are the targets for zled/smoothened). Of these, classes D and E are not found in with an extracellular N-terminus, an intracellular C-terminus and the majority of drugs in clinical usage [1451, 1560], although vertebrates. An alternative classification scheme "GRAFS" [1666] seven hydrophobic transmembrane domains (TM1-TM7) linked only a minority of these receptors are exploited therapeutically. divides vertebrate GPCRs into five classes, overlapping with the by three extracellular loops (ECL1-ECL3) and three intracellular The first classification scheme to be proposed for GPCRs [984] di- A-F nomenclature, viz: Searchable database: http://www.guidetopharmacology.org/index.jsp G-Protein-coupled receptors 5744 Full Contents of ConciseGuide: http://onlinelibrary.wiley.com/doi/10.1111/bph.13348/full S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 Glutamate family (class C), which includes metabotropic glutamate receptors, a calcium-sensing receptor and GABAB receptors, as well as three taste type 1 receptors [class C list] and a family of pheromone receptors (V2 receptors) that are abundant in rodents but absent in man [1309]. 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). [Class A list] 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 evolutionary ancient mofif also found in polycystic kidney disease 1 (PKD1)-like proteins, which has been suggested to be both required and sufficient for autoproteolysis [1538]. [Adhesion family list]. Frizzled family (class F) consists of 10 Frizzled proteins (FZD(1-10)) and Smoothened (SMO). [Frizzled family list]. 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 (class B), 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) [703]. GPCR families Family ClassA ClassB(Secretin) ClassC(Glutamate) Adhesion Frizzled Receptors with known ligands 197a 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 [396]; b[1443]; c[1309]; d[1866]. 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 the β2 adrenoceptor, the latter culminating in the award of the 2012 Nobel Prize in chemistry to Robert Lefkowitz and Brian Kobilka [975, 1073]. Family structure 5746 Orphan and other 7TM receptors 5780 Bradykinin receptors 5803 GABAB receptors 5746 Class A Orphans 5781 Calcitonin receptors 5805 Galanin receptors 5756 Class C Orphans 5783 Calcium-sensing receptors 5806 Ghrelin receptor 5756 Taste 1 receptors 5784 Cannabinoid receptors 5807 Glucagon receptor family 5757 Taste 2 receptors 5785 Chemerin receptor 5809 Glycoprotein hormone receptors 5758 Other 7TM proteins 5785 Chemokine receptors 5810 Gonadotrophin-releasing hormone receptors 5759 5-Hydroxytryptamine receptors 5791 Cholecystokinin receptors 5811 GPR18, GPR55 and GPR119 5764 Acetylcholine receptors (muscarinic) 5792 Class Frizzled GPCRs 5812 Histamine receptors 5766 Adenosine receptors 5793 Complement peptide receptors 5814 Hydroxycarboxylic acid receptors 5768 Adhesion Class GPCRs 5795 Corticotropin-releasing factor receptors 5815 Kisspeptin receptor 5770 Adrenoceptors 5796 Dopamine receptors 5816 Leukotriene receptors 5774 Angiotensin receptors 5798 Endothelin receptors 5818 Lysophospholipid (LPA) receptors 5775 Apelin receptor 5799 G protein-coupled estrogen receptor 5819 Lysophospholipid (S1P) receptors 5777 Bile acid receptor 5800 Formylpeptide receptors 5820 Melanin-concentrating hormone receptors 5778 Bombesin receptors 5801 Free fatty acid receptors 5821 Melanocortin receptors Searchable database: http://www.guidetopharmacology.org/index.jsp G-Protein-coupled receptors 5745 Full Contents of ConciseGuide: http://onlinelibrary.wiley.com/doi/10.1111/bph.13348/full S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 5822 Melatonin receptors 5835 Orexin receptors 5846 Relaxin family peptide receptors 5823 Metabotropic glutamate receptors 5836 Oxoglutarate receptor 5848 Somatostatin receptors 5826 Motilin receptor 5836 P2Y receptors 5850 Succinate receptor 5827 Neuromedin U receptors