Modulation of GABAA Receptor Function by G Protein-coupled 5-HT2C Receptors

Abstract

Two classical neurotransmitters, 5-hydroxytryptamine (5-HT) and GABA, coexist in neurons of the medulla oblongata, and activation of 5-HT receptors modulates GABAA receptor function in neurons of the ventral tegmental area, substantia nigra and cerebellum. We now report that activation of 5-HT2C receptors produces a long-lasting (20–90 min) inhibition of GABAA receptors in Xenopus oocytes coexpressing both types of receptors. 5-HT2C receptors caused a ∼ 60% decrease in the GABAA receptor Emax without affecting the EC50 or Hill coefficient. Intracellular microinjection of 500 μM BAPTA blocked, whereas microinjection of inositol 1,4,5-triphosphate mimicked the inhibitory action of 5-HT2C receptors. The inhibition was independent of the GABAA receptors subunit composition; receptors containing α2β1, α1β1, α1β1γ2L, and α2β1γ2S were inhibited to the same extent by 5-HT2C receptor activation. Moreover, GABAA receptors composed of wild-type α2 plus mutant β1(S409A) subunits were inhibited to the same extent as wild-type receptors. The nonspecific protein kinase inhibitor, staurosporine, and the inhibitor of serine/threonine protein phosphatases, calyculin A, did not block the inhibitory effects of 5-HT2C receptors. The results with these inhibitors, taken together with those obtained with GABAA receptors with different subunit compositions, suggest that protein kinases or serine/threonine phosphatases are not involved in this GABAA receptor modulatory process. Thus, we propose that 5-HT2C receptors inhibit GABAA receptors by a Ca2+-dependent, but phosphorylation independent, mechanism and that 5-HT and GABA may act as cotransmitters to regulate neuronal activity. Furthermore, disruption of the cross-talk between these receptors may play a role in the anti-anxiety actions of 5-HT2 receptor antagonists. Copyright © 1996 Elsevier Science Ltd