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     ASSOCIATE EDITOR: DAVID R. SIBLEY 

    The Physiology, Signaling, and Pharmacology of 

    Dopamine Receptors

    Jean-Martin Beaulieu and Raul R. Gainetdinov

     Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval–Centre de Recherche de l’Université Laval

     Robert-Giffard, Québec-City, Québec, Canada (J.-M.B.) and Department of Neuroscience and Brain Technologies, Italian Institute of 

    Technology, Genova, Italy (R.R.G.)

     Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183

    I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 II. Dopamine receptors: classification, genes, structure, expression, and functions . . . . . . . . . . . . . . . . 184

     A. Basic genetic and structural properties of dopamine receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 B. Dopamine receptor expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185

    C. Dopamine receptor functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 III. General principles of dopamine receptor signal transduction and regulation . . . . . . . . . . . . . . . . . . . 188

     A. Mechanisms of G protein-mediated signaling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 B. Inactivation of G proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188

    C. Involvement of  -arrestins/G protein-coupled receptor kinases in receptor regulation . . . . . . . 188 D. Heterologous desensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

    IV. Dopamine receptor signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

     A. cAMP, protein kinase A, DARPP-32, and associated proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 1. Amplification of protein kinase A signaling by DARPP-32 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

    2. Metabotropic neurotoxicity of cAMP-mediated dopamine receptor signaling . . . . . . . . . . . . . 191 3. Coincidence detection by mitogen-activated protein kinases. . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

    4. Interaction with Epac proteins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

    B. Alternative G protein mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1941. Receptor signaling through Gq. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 2. Regulation of G  signaling and ion channels by D2 dopamine receptors . . . . . . . . . . . . . . . 194

    C. Regulation of G protein activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 1. Evidence for the involvement of regulators of G protein signaling . . . . . . . . . . . . . . . . . . . . . . 196

    2. Evidence for additional regulatory mechanisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 D. Direct interactions with ion channels and associated proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

    1. Interactions with calcium channels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 2. Direct interactions with ionotropic receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

    E.   -Arrestins/G protein-coupled receptor kinases: from dopamine receptor desensitization to signaling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

    1. G protein-coupled receptor kinases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 2.   -Arrestins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

    F.   -Arrestin-mediated signaling and the regulation of Akt by dopamine . . . . . . . . . . . . . . . . . . . . . 200 1. Role of the -arrestin 2/Akt/glycogen synthase kinase 3 pathway in D2 dopamine

    receptor-mediated functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200 2. Two signaling modalities of slow synaptic transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

    3. Glycogen synthase kinase-3 targets involved in the effects of dopamine . . . . . . . . . . . . . . . . . 202  V. Pharmacology of dopamine receptors and human diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

     A. Abnormalities in dopamine receptor physiology in human disorders . . . . . . . . . . . . . . . . . . . . . . . 203 B. Abnormalities in G protein-related dopamine signaling in human disorders . . . . . . . . . . . . . . . . 204

     Address correspondence to: Raul R. Gainetdinov, Italian Institute of Technology (IIT), Via Morego 30, Genova, 16163, Italy. E-mail: raul.gainetdinov@iit.it

    J.M.B. and R.R.G. contributed equally to this work. This article is available online at http://pharmrev.aspetjournals.org.

    doi:10.1124/pr.110.002642.

    0031-6997/11/6301-182–217$20.00 PHARMACOLOGICAL REVIEWS   Vol. 63, No. 1 Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics 2642/3671136  Pharmacol Rev  63:182–217, 2011   Printed in U.S.A.

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    C. Abnormalities in  -arrestin 2/Akt/glycogen synthase kinase-3 signaling in human

    disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 D. Current and future dopaminergic treatments: a shift from receptor pharmacology to the

    targeting of postreceptor mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206 E. Biased ligand pharmacology of dopamine receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208

     VI. Summary and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209  Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211

    References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211

     Abstract——G protein-coupled dopamine receptors (D1, D2, D3, D4, and D5) mediate all of the physiologi- cal functions of the catecholaminergic neurotransmit- ter dopamine, ranging from voluntary movement and reward to hormonal regulation and hypertension. Pharmacological agents targeting dopaminergic neu- rotransmission have been clinically used in the man- agement of several neurological and psychiatric disor- ders, including Parkinson’s disease, schizophrenia, bipolar disorder, Huntington’s disease, attention defi- cit hyperactivity disorder (ADHD1), and Tourette’s syndrome. Numerous advances have occurred in un- derstanding the general structural, biochemical, and functional properties of dopamine receptors that have led to the development of multiple pharmacologically active compounds that directly target dopamine re- ceptors, such as antiparkinson drugs and antipsychot- ics. Recent progress in understanding the complex biol- ogy of dopamine receptor-related signal transduction mechanisms has revealed that, in addition to their pri- mary action on cAMP-mediated signaling, dopamine re-

    ceptors can act through diverse signali