Browsing by Author "Harris, RA"

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    Modulation of GABA(A) receptor function by G protein-coupled 5-HT2C receptors
    (1996) HuidobroToro, JP; Valenzuela, CF; Harris, RA
    Two classical neurotransmitters, 5-hydroxytryptamine (5-HT) and GABA, coexist in neurons of the medulla oblongata, and activation of 5-HT receptors modulates GABA(A) 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 GABA(A) receptors in Xenopus oocytes coexpressing both types of receptors. 5-HT2C receptors caused a similar to 60% decrease in the GABA(A) receptor E(max) without affecting the EC(50) or Hill coefficient. Intracellular microinjection of 500 mu M BAPTA blocked, whereas microinjection of inositol 1,4,5-triphosphate mimicked the inhibitory action of 5-HT2C receptors. The inhibition was independent of the GABA(A) receptors subunit composition; receptors containing alpha 2 beta 1, alpha 1 beta 1, alpha 1 beta 1 gamma 2L, and alpha 2 beta 1 gamma 2S were inhibited to the same extent by 5-HT2C receptor activation. Moreover, GABA(A) receptors composed of wild-type alpha 2 plus mutant beta 1((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 GABA(A) receptors with different subunit compositions, suggest that protein kinases or serine/threonine phosphatases are not involved in this GABA(A) receptor modulatory process. Thus, we propose that 5-HT2C receptors inhibit GABA(A) 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 antianxiety actions of 5-HT2 receptor antagonists. Copyright (C) 1996 Elsevier Science Ltd.