Catalytic Receptors
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S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2013/14: Catalytic Receptors. British Journal of Pharmacology (2013) 170, 1676–1705 THE CONCISE GUIDE TO PHARMACOLOGY 2013/14: CATALYTIC RECEPTORS Stephen P.H. Alexander*1, Helen E. Benson2, Elena Faccenda2, Adam J. Pawson2, Joanna L. Sharman2, Michael Spedding3, John A. Peters4, Anthony J. Harmar2 and IUPHAR International Union of Basic CGTP Collaborators and Clinical Pharmacology *Author for correspondence; [email protected] 1 School of Life Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, UK L 2The University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, UK 3 Spedding Research Solutions SARL, Le Vésinet 78110, France N 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK Abstract The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 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.12444/full. Catalytic receptors are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, ion channels, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. 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 the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates. An Introduction to Catalytic Receptors Catalytic receptors are cell-surface proteins, usually dimeric in Amongst the catalytic receptors, particular subfamilies may be GDNF receptor families, where one, catalytically silent, member nature, which typically encompass ligand binding and func- readily identified dependent on the function of the enzymatic of the heterodimer is activated upon binding the ligand, causing tional domains in one polypeptide chain. The ligand binding portion of the receptor. The smallest group is the particulate the second member of the heterodimer, lacking ligand binding domain is placed on the extracellular surface of the plasma mem- guanylyl cyclases of the natriuretic peptide receptor family. The capacity, to initiate signaling through tyrosine phosphorylation. brane and separated from the functional domain by a single most widely recognized group is probably the receptor tyrosine A fourth group, the receptor threonine/serine kinase (RTSK) transmembrane-spanning domain of 20-25 hydrophobic amino kinase (RTK) family, epitomized by the neurotrophin receptor family, exemplified by TGF-β and BMP receptors, has intrinsic acids. The functional domain on the intracellular face of the family, where a crucial initial step is the activation of a signalling serine/threonine protein kinase activity in the heterodimeric plasma membrane has catalytic activity, or interacts with particu- cascade by autophosphorylation of the receptor on intracellular functional unit. A fifth group is the receptor tyrosine phos- lar enzymes, giving the superfamily of receptors its name. Endog- tyrosine residue(s) catalyzed by enzyme activity intrinsic to the phatases (RTP), which generally appear to lack cognate ligands, enous agonists of the catalytic receptor superfamily are peptides receptor. A third group is the extrinsic protein tyrosine kinase but may be triggered by events such as cell:cell contact and have or proteins, the binding of which may induce dimerization of the receptors, where the catalytic activity resides in a separate identified roles in the skeletal, hematopoietic and immune receptor, which is the functional version of the receptor. protein from the binding site. Examples of this group include the systems. Searchable database: http://www.guidetopharmacology.org/index.jsp Catalytic receptors 1676 Full Contents of Concise Guide: http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2013/14: Catalytic Receptors. British Journal of Pharmacology (2013) 170, 1676–1705 A new group of catalytic receptors for the Guide is the integrins, which have roles in cell : cell communication, often associated with signalling in the blood. Acknowledgements We wish to acknowledge the tremendous help provided by the Consultants to the Guides past and present (see list in the Overview, p. 1452). We are extremely grateful for the financial contributions from the British Pharmacological Society, the International Union of Basic and Clinical Pharmacology, the Wellcome Trust (099156/Z/12/Z]), which support the website and the University of Edinburgh, who host the guidetopharmacology.org website. Conflict of interest The authors state that there is no conflict of interest to disclose. List of records presented 1678 Cytokine receptor family 1684 GDNF receptor family 1685 Integrins 1688 Natriuretic peptide receptor family 1689 Pattern Recognition receptors 1692 Receptor serine/threonine kinase (RSTK) family 1695 Receptor tyrosine kinases 1702 Receptor tyrosine phosphatases (RTP) 1703 Tumour necrosis factor (TNF) receptor family Searchable database: http://www.guidetopharmacology.org/index.jsp Catalytic receptors 1677 Full Contents of Concise Guide: http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2013/14: Catalytic Receptors. British Journal of Pharmacology (2013) 170, 1676–1705 Cytokine receptor family Overview: Cytokines are not a clearly defined group of agents, globulin (Ig)-like and fibronectin type III (FBNIII)-like domains, a thereby facilitate the recruitment of signal transducers and acti- other than having an impact on immune signalling pathways, transmembrane domain, and intracellular homology domains. vators of transcription (STATs). The activated homo- or heterodi- although many cytokines have effects on other systems, such An unusual feature of this group of agents is the existence of meric STATs function principally as transcription factors in the as in development. A feature of some cytokines, which allows soluble and decoy receptors. These bind cytokines without allow- nucleus. them to be distinguished from hormones, is that they may be ing signalling to occur. A further attribute is the production of produced by “non-secretory” cells, for example, endothelial cells. endogenous antagonist molecules, which bind to the receptors Type I cytokine receptors are characterized by two pairs of Within the cytokine receptor family, some subfamilies may be selectively and prevent signalling. A commonality of these conserved cysteines linked via disulfide bonds and a C-terminal identified, which are described elsewhere in the Guide to PHAR- families of receptors is the ligand-induced homo- or hetero- WSXWS motif within their CHD. Type I receptors are commonly MACOLOGY, receptors for the TNF family, the TGF-β family and oligomerisation, which results in the recruitment of intracellular classified into five groups, based on sequence and structual the chemokines. Within this group of records are described Type protein partners to evoke cellular responses, particularly in homology of the receptor and its cytokine ligand, which is I cytokine receptors, typified by interleukin receptors, and Type II inflammatory or haematopoietic signalling. Although not an potentially more reflective of evolutionary relationships than an cytokine receptors, exemplified by interferon receptors. These exclusive signalling pathway, a common feature of the majority earlier scheme based on the use of common signal transducing receptors possess a conserved extracellular region, known as the of cytokine receptors is activation of the JAK/STAT pathway. This chains within a receptor complex. cytokine receptor homology domain (CHD), along with a range cascade is based around the protein tyrosine kinase activity of the of other structural modules, including extracellular immuno- Janus kinases (JAK), which phosphorylate the receptor and IL-2 receptor family Overview: The IL-2 receptor family consists of one or more ligand-selective subunits, and a common γ chain (γc): IL2RG, P31785), though IL-4 and IL-7 receptors can form complexes with other receptor chains. Receptors of this family associate with Jak1 and Jak3, primarily activating Stat5, although certain family members can also activate Stat1, Stat3, or Stat6. Ro264550 has been described as a selective IL-2 receptor antagonist, which binds to IL-2 [3]. Nomenclature Interleukin-2 receptor Interleukin-4 receptor type I Interleukin-4 receptor type II Interleukin-7 receptor Interleukin-9 receptor Subunits Interleukin-2