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Review ArticleReview Article

The Physiology, Signaling, and Pharmacology of Dopamine Receptors

Jean-Martin Beaulieu and Raul R. Gainetdinov
David R. Sibley, ASSOCIATE EDITOR
Pharmacological Reviews March 2011, 63 (1) 182-217; DOI: https://doi.org/10.1124/pr.110.002642
Jean-Martin Beaulieu
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.)
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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.)
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David R. Sibley
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.)
Roles: ASSOCIATE EDITOR
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Abstract

G protein-coupled dopamine receptors (D1, D2, D3, D4, and D5) mediate all of the physiological functions of the catecholaminergic neurotransmitter dopamine, ranging from voluntary movement and reward to hormonal regulation and hypertension. Pharmacological agents targeting dopaminergic neurotransmission have been clinically used in the management of several neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, bipolar disorder, Huntington's disease, attention deficit hyperactivity disorder (ADHD1), and Tourette's syndrome. Numerous advances have occurred in understanding 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 receptors, such as antiparkinson drugs and antipsychotics. Recent progress in understanding the complex biology of dopamine receptor-related signal transduction mechanisms has revealed that, in addition to their primary action on cAMP-mediated signaling, dopamine receptors can act through diverse signaling mechanisms that involve alternative G protein coupling or through G protein-independent mechanisms via interactions with ion channels or proteins that are characteristically implicated in receptor desensitization, such as β-arrestins. One of the future directions in managing dopamine-related pathologic conditions may involve a transition from the approaches that directly affect receptor function to a precise targeting of postreceptor intracellular signaling modalities either directly or through ligand-biased signaling pharmacology. In this comprehensive review, we discuss dopamine receptor classification, their basic structural and genetic organization, their distribution and functions in the brain and the periphery, and their regulation and signal transduction mechanisms. In addition, we discuss the abnormalities of dopamine receptor expression, function, and signaling that are documented in human disorders and the current pharmacology and emerging trends in the development of novel therapeutic agents that act at dopamine receptors and/or on related signaling events.

Footnotes

  • 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.

  • ↵1 Abbreviations:

    AC
    adenylate cyclase
    ACR16
    huntexil
    ADHD
    attention deficit hyperactivity disorder
    AMPA
    α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
    BAC
    bacterial artificial chromosome
    BDNF
    brain-derived neurotrophic factor
    CDK5
    cyclin-dependent kinase 5
    CK
    casein kinase
    CREB
    cAMP response element-binding protein
    D2L
    D2-long
    D2S
    D2-short
    DAG
    diacylglycerol
    DARPP-32
    32-kDa dopamine and cAMP-regulated phosphoprotein
    DAT
    dopamine transporter
    Epac
    exchange proteins directly activated by cAMP
    ERK
    extracellular-signal regulated kinase 1 and 2
    GIRK
    G protein-coupled inwardly rectifying potassium channel
    GPCR
    G protein-coupled receptor
    GRK
    G protein-coupled receptor kinase
    GSK-3
    glycogen synthase kinase 3
    HEK
    human embryonic kidney
    IP3
    inositol trisphosphate
    KO
    knockout
    LTD
    long-term depression
    MAP
    mitogen-activated protein
    MEK
    MAP/ERK kinase
    MK-801
    dizocilpine maleate
    MSN
    medium spiny neuron
    NCS-1
    neuronal calcium sensor-1
    NMDA
    N-methyl-d-aspartate
    OSU6162
    (3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride
    Par-4
    prostate apoptosis response-4
    PD
    Parkinson's disease
    PKA
    protein kinase A
    PKC
    protein kinase C
    PLC
    phospholipase C
    PP1
    protein phosphatase 1
    PP2A
    protein phosphatase 2A
    PP2B
    protein phosphatase 2B
    PSD-95
    postsynaptic density-95
    RGS
    regulators of G protein signaling
    SCH23390
    7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol
    SL327
    α-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile
    STEP
    striatal-enriched tyrosine phosphatase
    WT
    wild type.

  • © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 63 (1)
Pharmacological Reviews
Vol. 63, Issue 1
1 Mar 2011
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Review ArticleReview Article

The Physiology, Signaling, and Pharmacology of Dopamine Receptors

Jean-Martin Beaulieu and Raul R. Gainetdinov
Pharmacological Reviews March 1, 2011, 63 (1) 182-217; DOI: https://doi.org/10.1124/pr.110.002642

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Review ArticleReview Article

The Physiology, Signaling, and Pharmacology of Dopamine Receptors

Jean-Martin Beaulieu and Raul R. Gainetdinov
Pharmacological Reviews March 1, 2011, 63 (1) 182-217; DOI: https://doi.org/10.1124/pr.110.002642
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  • Article
    • Abstract
    • I. Introduction
    • II. Dopamine Receptors: Classification, Genes, Structure, Expression, and Functions
    • III. General Principles of Dopamine Receptor Signal Transduction and Regulation
    • IV. Dopamine Receptor Signaling
    • V. Pharmacology of Dopamine Receptors and Human Diseases
    • VI. Summary and Future Directions
    • Authorship Contributions
    • Acknowledgments
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