GAMMA-AMINOBUTYRIC ACID(A) RECEPTOR FUNCTION IS INHIBITED BY MICROTUBULE DEPOLYMERIZATION

Microtubules are present at postsynaptic densities in brain and are pr oposed to be involved in anchoring neurotransmitter receptor clusters at postsynaptic membranes. However, the influence of microtubules on g amma-aminobutyric acid(A) (GABA(A)) receptors has not been studied. Mi crotubule-affecting agents were tested for their actions on GABA(A) re ceptor function, by measuring muscimol-stimulated chloride uptake into cerebral cortical microsacs and proteoliposomes and GABA-mediated cur rents in Xenopus laevis oocytes expressing GABA(A) receptors. Colchici ne, nocodazole, vinblastine, and taxol inhibited muscimol-stimulated c hloride uptake. beta- and gamma-lumicolchicine did not inhibit GABA(A) ergic function. Colchicine decreased the potency of muscimol, a GABA a gonist, to stimulate chloride uptake without affecting the specific bi nding of [H-3]flunitrazepam or t-[S-35]butylbicyclophosphorothionate t o the GABA(A) receptor, or the allosteric modulation of binding of the se ligands by muscimol. The function of purified GABA(A) receptors rec onstituted in proteoliposomes, a preparation not containing microtubul e components, was not affected by colchicine. In contrast to the resul ts seen in human monocytes by other investigators, we found that colch icine decreased, rather than increased, protein kinase A activity in c ortical microsacs. Thus, protein kinase A modulation of the GABA(A) re ceptor is not a likely mechanism for the actions of colchicine. We pro pose that microtubule-depolymerizing agents inhibit GABA(A)ergic funct ion by disrupting the interaction of GABA(A) receptors with microtubul es.