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

Fang Liu, Qi Wan, Zdenek B. Pristupa, Xian-Min Yu, Yu Tian Wang () and Hyman B. Niznik ()
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Fang Liu: Department of Psychiatry
Qi Wan: Hospital for Sick Children
Zdenek B. Pristupa: Department of Psychiatry
Xian-Min Yu: Department of Psychiatry
Yu Tian Wang: Hospital for Sick Children
Hyman B. Niznik: Department of Psychiatry

Nature, 2000, vol. 403, issue 6767, 274-280

Abstract: 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.

Date: 2000
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DOI: 10.1038/35002014

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