Modulation of GABA A Receptor Function by G Protein-coupled 5-HT 2C Receptors

Modulation of GABA A Receptor Function by G Protein-coupled 5-HT 2C Receptors 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-HT 2C receptors produces a long-lasting (20–90 min) inhibition of GABA A receptors in Xenopus oocytes coexpressing both types of receptors. 5-HT 2C receptors caused a ∼ 60% decrease in the GABA A receptor E max without affecting the EC 50 or Hill coefficient. Intracellular microinjection of 500 μM BAPTA blocked, whereas microinjection of inositol 1,4,5-triphosphate mimicked the inhibitory action of 5-HT 2C receptors. The inhibition was independent of the GABA A receptors subunit composition; receptors containing α2β1, α1β1, α1β1γ2L, and α2β1γ2S were inhibited to the same extent by 5-HT 2C receptor activation. Moreover, GABA A 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-HT 2C 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-HT 2C receptors inhibit GABA A 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-HT 2 receptor antagonists. Copyright © 1996 Elsevier Science Ltd http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neuropharmacology Elsevier

Modulation of GABA A Receptor Function by G Protein-coupled 5-HT 2C Receptors

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Publisher
Elsevier
Copyright
Copyright © 1996 Elsevier Science Ltd
ISSN
0028-3908
eISSN
1873-7064
DOI
10.1016/S0028-3908(96)00084-6
Publisher site
See Article on Publisher Site

Abstract

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-HT 2C receptors produces a long-lasting (20–90 min) inhibition of GABA A receptors in Xenopus oocytes coexpressing both types of receptors. 5-HT 2C receptors caused a ∼ 60% decrease in the GABA A receptor E max without affecting the EC 50 or Hill coefficient. Intracellular microinjection of 500 μM BAPTA blocked, whereas microinjection of inositol 1,4,5-triphosphate mimicked the inhibitory action of 5-HT 2C receptors. The inhibition was independent of the GABA A receptors subunit composition; receptors containing α2β1, α1β1, α1β1γ2L, and α2β1γ2S were inhibited to the same extent by 5-HT 2C receptor activation. Moreover, GABA A 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-HT 2C 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-HT 2C receptors inhibit GABA A 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-HT 2 receptor antagonists. Copyright © 1996 Elsevier Science Ltd

Journal

NeuropharmacologyElsevier

Published: Jan 1, 1996

References

  • Noradrenaline receptors participate in the regulation of GABAergic inhibition in area CA1 of the rat hippocampus
    Andreasen, M; Lambert, J.D.C
  • 5-HT receptors as targets for the development of novel anxiolytic drugs: models, mechanism and future directions
    Barrett, J.E; Vanover, K.E
  • Serotonin-mediated inhibitory postsynaptic potential in guinea-pig prepositus hypoglossi and feedback inhibition by serotonin
    Bobker, D.H; Williams, J.T
  • Activation of metabotropic glutamate receptors induces long-term depression of GABAergic inhibition in hippocampus
    Liu, Y.B; Disterhoft, J.F; Slater, T
  • 5-HT-mediated synaptic potentials in the dorsal raphe nucleus: interactions with excitatory amino acid and GABA neurotransmission
    Pan, Z.Z; Colmers, W.F; Williams, J.T
  • Extent of colocalization of serotonin and GABA in the neurons of the rat raphe nuclei
    Stamp, J.A; Semba, K
  • Staurosporine: an effective inhibitor for Ca 2+ /calmodulin-dependent protein kinase II
    Yanagihara, N; Tachikawa, E; Izumi, F; Yasugawa, S; Yamamoto, H; Miyamoto, E

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