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MIT 7 61 - Research Paper

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ISSN: 1524-4571 Copyright © 2006 American Heart Association. All rights reserved. Print ISSN: 0009-7330. OnlineTX 72514Circulation Research is published by the American Heart Association. 7272 Greenville Avenue, Dallas,DOI: 10.1161/01.RES.0000242563.47507.ce 2006;99;570-582 Circ. Res.Matthew T. Drake, Sudha K. Shenoy and Robert J. Lefkowitz Trafficking of G Protein–Coupled Receptors http://circres.ahajournals.org/cgi/content/full/99/6/570located on the World Wide Web at: The online version of this article, along with updated information and services, is http://www.lww.com/static/html/reprints.htmlReprints: Information about reprints can be found online at [email protected], Baltimore, MD 21202-2436. Phone 410-5280-4050. Fax: 410-528-8550. Email: Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, 351 West Camden http://circres.ahajournals.org/subsriptions/Subscriptions: Information about subscribing to Circulation Research is online at at Massachusetts Institute o on September 14, 2006 circres.ahajournals.orgDownloaded fromThis Review is part of a thematic series on Microdomains in Cardiovascular Signaling, which includes thefollowing articles:Caveolae and Caveolins in the Cardiovascular SystemFocal Adhesion: Paradigm for a Signaling NexusVesicular Trafficking of Tyrosine Kinase Receptors and Associated Proteins in the Regulation of Signaling andVascular FunctionCompartmentation of Cyclic Nucleotide Signaling in the Heart: The Role of A-Kinase Anchoring ProteinsTrafficking of G Protein–Coupled ReceptorsCompartmentation of Cyclic Nucleotide Signaling in the Heart: The Role of Cyclic Nucleotide PhosphodiesterasesKathy K. Griendling and David A. Kass, EditorsTrafficking of G Protein–Coupled ReceptorsMatthew T. Drake, Sudha K. Shenoy, Robert J. LefkowitzAbstract—G protein–coupled receptors (GPCRs) play an integral role in the signal transduction of an enormous array ofbiological phenomena, thereby serving to modulate at a molecular level almost all components of human biology. Thisrole is nowhere more evident than in cardiovascular biology, where GPCRs regulate such core measures ofcardiovascular function as heart rate, contractility, and vascular tone. GPCR/ligand interaction initiates signaltransduction cascades, and requires the presence of the receptor at the plasma membrane. Plasma membrane localizationis in turn a function of the delivery of a receptor to and removal from the cell surface, a concept defined most broadlyas receptor trafficking. This review illuminates our current view of GPCR trafficking, particularly within thecardiovascular system, as well as highlights the recent and provocative finding that components of the GPCR traffickingmachinery can facilitate GPCR signaling independent of G protein activation. (Circ Res. 2006;99:570-582.)Key Words: GPCR䡲trafficking䡲GPCR kinase (GRK)䡲␤-arrestin䡲7-transmembrane receptorsGprotein– coupled receptors (GPCRs) are central media-tors of nearly all aspects of cardiovascular biology.GPCRs were originally identified as receptors capable ofcoupling to specific guanine nucleotide-binding proteins (Gproteins), thereby transducing an extracellular signal to anintracellular effector, although more recently, several GPCRshave been demonstrated to signal via G protein–independentmechanisms both in vitro and in vivo.1As a family ofproteins, GPCRs share common structural features, includingseven membrane-spanning domains, and thus are alterna-tively referred to as 7-transmembrane receptors. GPCRs arethe largest superfamily of cell-surface receptors, accountingfor approximately 2% of the human genome.2Further, li-gands directed at GPCRs (primarily agonists and antagonists)represent the largest family of pharmacological agents, ac-counting for nearly 30% of current clinical pharmaceuticalagents available.3Both hormones and neurotransmitters exerttheir effects on the cardiovascular system via GPCRs. Exam-ples of GPCRs with well-ascribed roles in cardiovascularbiology include the␤1- and␤2-adrenergic receptors (ARs),the␣1- and␣2-ARs, the M2- and M3-muscarinic acetylcholinereceptors, the angiotensin II (Ang II) receptors, the endothelinreceptors, the adenosine receptor, the thrombin receptor, andthe vasopressin receptor.Over the past nearly 3 decades, a wealth of information hasrevealed much about the signaling properties of this family ofseven membrane-spanning receptors. Much work has focusedon revealing the ways in which the GPCRs regulate discreteeffector molecules including adenylyl cyclase, phospho-lipases, and ion channels. Still further work has shed light onOriginal received June 30, 2006; revision received August 10, 2006; accepted August 11, 2006.From the Howard Hughes Medical Institute and Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, NC.Correspondence to Robert Lefkowitz, Box 3821, Duke University Medical Center, Durham, NC 27710. E-mail [email protected]© 2006 American Heart Association, Inc.Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/01.RES.0000242563.47507.ce570Reviewmechanisms by which GPCR signaling is regulated and has ledto the discovery of additional proteins including the GPCRkinases (GRKs)4,5and␤-arrestin proteins,6,7which respectivelyphosphorylate agonist-activated GPCRs and bind phosphorylat-ed GPCRs to physically disrupt the receptor/G protein interac-tion, thereby leading to desensitization of receptor-mediated Gprotein activation. In addition to its role in GPCR desensitiza-tion,␤-arrestin binding also promotes the cytosol to cell surfacetranslocation of components of the endocytic machinery, namelyadaptor protein-2 (AP-2)8and clathrin,9thereby facilitatingreceptor removal from the plasma membrane.Although still substantial, comparatively less work hasfocused on GPCR trafficking, much of it related to mecha-nisms regulating endocytosis of GPCRs from the cellularsurface, including the role of␤-arrestin in facilitating GPCRendocytosis as above. Indeed, the appropriate delivery ofGPCRs to the cell surface to permit receptor/ligand interac-tions, and their subsequent retrieval from the plasma mem-brane, are of fundamental importance for the regulation ofGPCR activity. This review highlights our current under-standing of GPCR movement from synthesis onward, withspecial emphasis on studies of GPCRs from the cardiovascu-lar system. Lastly, we discuss the


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MIT 7 61 - Research Paper

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