Modulation of GABAA receptor function by G protein-coupled 5-HT2C receptors.
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 approximately 60% decrease in the GABAA receptor Emax without affecting the EC50 or Hill coefficient. Intracellular microinjection of 500 microM 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 alpha 2 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, GABAA 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 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 Ca(2+)-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.
Huidobro-Toro
J P
JP
Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262, USA.
Valenzuela
C F
CF
Harris
R A
RA
D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D008387:Marine Toxins; D009865:Oocytes / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis; D011963:Receptors, GABA-A / Q000096:biosynthesis / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000096:biosynthesis / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D014158:Transcription, Genetic; D014982:Xenopus laevis
D002614:Chelating Agents; D018118:Chloride Channels; D004791:Enzyme Inhibitors; D008387:Marine Toxins; D010080:Oxazoles; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D011985:Receptors, Serotonin; D004533:Egtazic Acid; C059041:calyculin A; D010749:Phosphoprotein Phosphatases; D019204:GTP-Binding Proteins; D019311:Staurosporine; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid