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      International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin 1) and GPR1 (Chemerin 2) Nomenclature, Pharmacology, and Function

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          Abstract

          Chemerin, a chemoattractant protein and adipokine, has been identified as the endogenous ligand for a G protein–coupled receptor encoded by the gene CMKLR1 (also known as ChemR23), and as a consequence the receptor protein was renamed the chemerin receptor in 2013. Since then, chemerin has been identified as the endogenous ligand for a second G protein–coupled receptor, encoded by the gene GPR1. Therefore, the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification recommends that the official name of the receptor protein for chemokine-like receptor 1 (CMKLR1) is chemerin receptor 1, and G protein–coupled receptor 1 is chemerin receptor 2 to follow the convention of naming the receptor protein after the endogenous ligand. Chemerin receptor 1 and chemerin receptor 2 can be abbreviated to Chemerin 1 and Chemerin 2, respectively. Chemerin requires C-terminal processing for activity, and human chemerin21–157 is reported to be the most active form, with peptide fragments derived from the C terminus biologically active at both receptors. Small-molecule antagonist, CCX832, selectively blocks CMKLR1, and resolvin E1 activation of CMKLR1 is discussed. Activation of both receptors by chemerin is via coupling to G i/o, causing inhibition of adenylyl cyclase and increased Ca 2+ flux. Receptors and ligand are widely expressed in humans, rats, and mice, and both receptors share ∼80% identity across these species. CMKLR1 knockout mice highlight the role of this receptor in inflammation and obesity, and similarly, GPR1 knockout mice exhibit glucose intolerance. In addition, the chemerin receptors have been implicated in cardiovascular disease, cancer, steroidogenesis, human immunodeficiency virus replication, and neurogenerative disease.

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          Heterotrimeric G protein activation by G-protein-coupled receptors.

          Heterotrimeric G proteins have a crucial role as molecular switches in signal transduction pathways mediated by G-protein-coupled receptors. Extracellular stimuli activate these receptors, which then catalyse GTP-GDP exchange on the G protein alpha-subunit. The complex series of interactions and conformational changes that connect agonist binding to G protein activation raise various interesting questions about the structure, biomechanics, kinetics and specificity of signal transduction across the plasma membrane.
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            Specific Recruitment of Antigen-presenting Cells by Chemerin, a Novel Processed Ligand from Human Inflammatory Fluids

            Dendritic cells (DCs) and macrophages are professional antigen-presenting cells (APCs) that play key roles in both innate and adaptive immunity. ChemR23 is an orphan G protein–coupled receptor related to chemokine receptors, which is expressed specifically in these cell types. Here we present the characterization of chemerin, a novel chemoattractant protein, which acts through ChemR23 and is abundant in a diverse set of human inflammatory fluids. Chemerin is secreted as a precursor of low biological activity, which upon proteolytic cleavage of its COOH-terminal domain, is converted into a potent and highly specific agonist of ChemR23, the chemerin receptor. Activation of chemerin receptor results in intracellular calcium release, inhibition of cAMP accumulation, and phosphorylation of p42–p44 MAP kinases, through the Gi class of heterotrimeric G proteins. Chemerin is structurally and evolutionary related to the cathelicidin precursors (antibacterial peptides), cystatins (cysteine protease inhibitors), and kininogens. Chemerin was shown to promote calcium mobilization and chemotaxis of immature DCs and macrophages in a ChemR23-dependent manner. Therefore, chemerin appears as a potent chemoattractant protein of a novel class, which requires proteolytic activation and is specific for APCs.
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              Chemerin, a novel adipokine that regulates adipogenesis and adipocyte metabolism.

              Obesity is an alarming primary health problem and is an independent risk factor for type II diabetes, cardiovascular diseases, and hypertension. Although the pathologic mechanisms linking obesity with these co-morbidities are most likely multifactorial, increasing evidence indicates that altered secretion of adipose-derived signaling molecules (adipokines; e.g. adiponectin, leptin, and tumor necrosis factor alpha) and local inflammatory responses are contributing factors. Chemerin (RARRES2 or TIG2) is a recently discovered chemoattractant protein that serves as a ligand for the G protein-coupled receptor CMKLR1 (ChemR23 or DEZ) and has a role in adaptive and innate immunity. Here we show an unexpected, high level expression of chemerin and its cognate receptor CMKLR1 in mouse and human adipocytes. Cultured 3T3-L1 adipocytes secrete chemerin protein, which triggers CMKLR1 signaling in adipocytes and other cell types and stimulates chemotaxis of CMKLR1-expressing cells. Adenoviral small hairpin RNA targeted knockdown of chemerin or CMKLR1 expression impairs differentiation of 3T3-L1 cells into adipocytes, reduces the expression of adipocyte genes involved in glucose and lipid homeostasis, and alters metabolic functions in mature adipocytes. We conclude that chemerin is a novel adipose-derived signaling molecule that regulates adipogenesis and adipocyte metabolism.
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                Author and article information

                Contributors
                Role: ASSOCIATE EDITOR
                Journal
                Pharmacol Rev
                Pharmacol. Rev
                pharmrev
                Pharmacol Rev
                PharmRev
                Pharmacological Reviews
                The American Society for Pharmacology and Experimental Therapeutics (Bethesda, MD )
                0031-6997
                1521-0081
                January 2018
                January 2018
                January 2018
                : 70
                : 1
                : 174-196
                Affiliations
                [1]Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke’s Hospital, Cambridge, United Kingdom
                Author notes
                Address correspondence to: Dr. Anthony P. Davenport, Experimental Medicine and Immunotherapeutics, University of Cambridge, Level 6, Addenbrooke's Centre For Clinical Investigation, Box 110, Addenbrooke’s Hospital, CB2 0QQ Cambridge, UK. E-mail: apd10@ 123456medschl.cam.ac.uk
                Article
                PHARMREV_013177
                10.1124/pr.116.013177
                5744648
                29279348
                00c38e6b-fbca-4d94-89b2-38cdc8622ca0
                Copyright © 2017 by The Author(s)

                This is an open access article distributed under the CC BY Attribution 4.0 International license.

                History
                Page count
                Figures: 7, Tables: 4, Equations: 0, References: 148, Pages: 23
                Categories
                IUPHAR Nomenclature Report
                Custom metadata
                v1

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