Direct protein-protein coupling enables cross-talk between dopamine D5 and gamma-aminobutyric acid A receptors.
GABA(A) (gamma-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 GABA(A) receptor function, through the activation of second-messenger signalling cascades by G proteins. Here we show that GABA(A)-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 GABA(A) gamma2(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.
Pubmed ID: 10659839 RIS Download
Amino Acid Motifs | Animals | Benzazepines | Cell Line | Cells, Cultured | Cyclic AMP | Dopamine | Dopamine Agonists | GABA-A Receptor Agonists | GABA-A Receptor Antagonists | Hippocampus | Humans | Ligands | Neurons | Rats | Receptor Cross-Talk | Receptors, Dopamine D1 | Receptors, Dopamine D5 | Receptors, GABA-A | Recombinant Fusion Proteins | Synaptic Transmission | Transfection | gamma-Aminobutyric Acid