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Direct protein–protein coupling enables cross-talk between dopamine D5 and γ-aminobutyric acid A receptors

Naturevolume 403, pages274–280 (2000)Cite this article

Abstract

GABAA (γ-aminobutyric-acid A) and dopamine D1 and D5 receptors represent two structurally and functionally divergent families of neurotransmitter receptors. The former comprises a class of multi-subunit ligand-gated channels mediating fast interneuronal synaptic transmission, whereas the latter belongs to the seven-transmembrane-domain single-polypeptide receptor superfamily that exerts its biological effects, including the modulation of GABAA receptor function, through the activation of second-messenger signalling cascades by G proteins. Here we show that GABAA-ligand-gated channels complex selectively with D5 receptors through the direct binding of the D5 carboxy-terminal domain with the second intracellular loop of the GABAA γ2(short) receptor subunit. This physical association enables mutually inhibitory functional interactions between these receptor systems. The data highlight a previously unknown signal transduction mechanism whereby subtype-selective G-protein-coupled receptors dynamically regulate synaptic strength independently of classically defined second-messenger systems, and provide a heuristic framework in which to view these receptor systems in the maintenance of psychomotor disease states.

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Figure 1: Association of D5 and GABAA receptors in rat brain and in vitro.
Figure 2: Selective modulation of dopamine-mediated D5 receptor-stimulated cAMP accumulation by GABAA α1β2γ2 receptors in co-expressed HEK-293 cells.
Figure 3: GABAA receptor modulation of D5 cAMP production is dependent on γ2 subunit and D5-CT sequences in co-expressed cells.
Figure 4: D5 receptor regulation of GABAA-receptor-mediated whole-cell currents in co-transfected HEK-293 cells.
Figure 5: Co-localization of GABAA and dopamine D5 receptors in cultured hippocampal neurons.
Figure 6: Dopamine D5 receptors modify GABAA-receptor-mediated synaptic responses in hippocampal neurons.

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Acknowledgements

We thank J. Braunton, K. M. Zhu and H. Y. Man for technical assistance. This work was supported by grants from NIDA, the Ontario Mental Health Foundation (H.B.N.) and the MRC of Canada (H.B.N., X.M.Y., Y.T.W.). F.L. was supported by a C. Cleghorn Fellowship in Schizophrenia Research and is a fellow of the Canadian Psychiatric Research Foundation; Z.B.P. is a NARSAD Young Investigator. X.M.Y. is an MRC Scholar and Y.T.W. is a Research Scholar of the Heart and Stroke Foundation of Canada. H.B.N. was supported in part by the C.B. Ireland Endowed Fund for Psychiatric Research.

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Authors and Affiliations

  1. Department of Psychiatry,

    Fang Liu, Zdenek B. Pristupa, Xian-Min Yu & Hyman B. Niznik

  2. Department of Pharmacology,

    Hyman B. Niznik

  3. Department of Oral Physiology,

    Xian-Min Yu

  4. Institute of Medical Sciences, University of Toronto, Toronto, M5S-1A8, Ontario, Canada

    Fang Liu & Hyman B. Niznik

  5. Program in Brain and Behavior and Division of Pathology, Hospital for Sick Children, Toronto, M5G 1X8, Ontario, Canada

    Qi Wan & Yu Tian Wang

  6. Molecular Neurobiology Section, Center for Addiction and Mental Health, Toronto, M5T 1R8, Ontario, Canada

    Fang Liu, Zdenek B. Pristupa, Xian-Min Yu & Hyman B. Niznik

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Correspondence toHyman B. Niznik.

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Liu, F., Wan, Q., Pristupa, Z.et al. Direct protein–protein coupling enables cross-talk between dopamine D5 and γ-aminobutyric acid A receptors.Nature403, 274–280 (2000). https://doi.org/10.1038/35002014

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