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Gs- versus Golf-dependent functional selectivity mediated by the dopamine D1 receptor

Author

Listed:
  • Hideaki Yano

    (National Institutes of Health)

  • Ning-Sheng Cai

    (National Institutes of Health)

  • Min Xu

    (National Institutes of Health)

  • Ravi Kumar Verma

    (National Institutes of Health)

  • William Rea

    (National Institutes of Health)

  • Alexander F. Hoffman

    (National Institutes of Health)

  • Lei Shi

    (National Institutes of Health)

  • Jonathan A. Javitch

    (Columbia University
    New York State Psychiatric Institute)

  • Antonello Bonci

    (National Institutes of Health)

  • Sergi Ferré

    (National Institutes of Health)

Abstract

The two highly homologous subtypes of stimulatory G proteins Gαs (Gs) and Gαolf (Golf) display contrasting expression patterns in the brain. Golf is predominant in the striatum, while Gs is predominant in the cortex. Yet, little is known about their functional distinctions. The dopamine D1 receptor (D1R) couples to Gs/olf and is highly expressed in cortical and striatal areas, making it an important therapeutic target for neuropsychiatric disorders. Using novel drug screening methods that allow analysis of specific G-protein subtype coupling, we found that, relative to dopamine, dihydrexidine and N-propyl-apomorphine behave as full D1R agonists when coupled to Gs, but as partial D1R agonists when coupled to Golf. The Gs/Golf-dependent biased agonism by dihydrexidine was consistently observed at the levels of cellular signaling, neuronal function, and behavior. Our findings of Gs/Golf-dependent functional selectivity in D1R ligands open a new avenue for the treatment of cortex-specific or striatum-specific neuropsychiatric dysfunction.

Suggested Citation

  • Hideaki Yano & Ning-Sheng Cai & Min Xu & Ravi Kumar Verma & William Rea & Alexander F. Hoffman & Lei Shi & Jonathan A. Javitch & Antonello Bonci & Sergi Ferré, 2018. "Gs- versus Golf-dependent functional selectivity mediated by the dopamine D1 receptor," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02606-w
    DOI: 10.1038/s41467-017-02606-w
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    Cited by:

    1. Mark J. Wall & Emily Hill & Robert Huckstepp & Kerry Barkan & Giuseppe Deganutti & Michele Leuenberger & Barbara Preti & Ian Winfield & Sabrina Carvalho & Anna Suchankova & Haifeng Wei & Dewi Safitri , 2022. "Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression," Nature Communications, Nature, vol. 13(1), pages 1-22, December.

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