gamma -Aminobutyric acid sub(A) receptor function is inhibited by microtubule depolymerization

Microtubules are present at postsynaptic densities in brain and are proposed to be involved in anchoring neurotransmitter receptor clusters at postsynaptic membranes. However, the influence of microtubules on gamma -aminobutyric acid sub(a) (GABA sub(A)) receptors has not been studied. Microtubule-a...

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Bibliographic Details
Published in:The Journal of biological chemistry 1994-01, Vol.269 (30), p.19546-19552
Main Authors: Whatley, V J, Mihic, S J, Allan, A M, McQuilkin, S J, Harris, R A
Format: Article
Language:English
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Xenopus laevis
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Summary:Microtubules are present at postsynaptic densities in brain and are proposed to be involved in anchoring neurotransmitter receptor clusters at postsynaptic membranes. However, the influence of microtubules on gamma -aminobutyric acid sub(a) (GABA sub(A)) receptors has not been studied. Microtubule-affecting agents were tested for their actions on GABA sub(A) receptor function, by measuring muscimol-stimulated chloride uptake into cerebral cortical microsacs and proteoliposomes and GABA-mediated currents in Xenopus laevis oocytes expressing GABA sub(A) receptors. Colchicine, nocodazole, vinblastine, and taxol inhibited muscimol-stimulated chloride uptake. beta - and gamma -lumicolchicine did not inhibit GABA sub(A)ergic function. Colchicine decreased the potency of muscimol, a GABA agonist, to stimulate chloride uptake without affecting the specific binding of [ super(3)H]flunitrazepam or t-[ super(35)S]butylbicyclophosphorothionate to the GABA sub(A) receptor, or the allosteric modulation of binding of these ligands by muscimol. The function of purified GABA sub(A) receptors reconstituted in proteoliposomes, a preparation not containing microtubule components, was not affected by colchicine. In contrast to the results seen in human monocytes by other investigators, we found that colchicine decreased, rather than increased, protein kinase A activity in cortical microsacs. Thus, protein kinase A modulation of the GABA sub(A) receptor is not a likely mechanism for the actions of colchicine. We propose that microtubule-depolymerizing agents inhibit GABA sub(A)ergic function by disrupting the interaction of GABA sub(A) receptors with microtubules.
ISSN:0021-9258