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.
Liu
F
F
Department of Psychiatry, University of Toronto, Ontario, Canada.
Wan
Q
Q
Pristupa
Z B
ZB
Yu
X M
XM
Wang
Y T
YT
Niznik
H B
HB
D020816:Amino Acid Motifs; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D020239:Receptor Cross-Talk; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D050641:Receptors, Dopamine D5; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology
D001552:Benzazepines; C493605:DRD5 protein, human; D018491:Dopamine Agonists; C493607:Drd5 protein, rat; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D008024:Ligands; D017447:Receptors, Dopamine D1; D011963:Receptors, GABA-A; D011993:Recombinant Fusion Proteins; D050641:Receptors, Dopamine D5; D005680:gamma-Aminobutyric Acid; C067113:SK&F 81297; D000242:Cyclic AMP; D004298:Dopamine