Gamma-aminobutyric acidA 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 acidA (GABAA) receptors has not been studied. Microtubule-affecting agents were tested for their actions on GABAA receptor function, by measuring muscimol-stimulated chloride uptake into cerebral cortical microsacs and proteoliposomes and GABA-mediated currents in Xenopus laevis oocytes expressing GABAA receptors. Colchicine, nocodazole, vinblastine, and taxol inhibited muscimol-stimulated chloride uptake. beta- and gamma-lumicolchicine did not inhibit GABAA ergic function. Colchicine decreased the potency of muscimol, a GABA agonist, to stimulate chloride uptake without affecting the specific binding of [3H]flunitrazepam or t-[35S]butylbicyclophosphorothionate to the GABAA receptor, or the allosteric modulation of binding of these ligands by muscimol. The function of purified GABAA 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 GABAA receptor is not a likely mechanism for the actions of colchicine. We propose that microtubule-depolymerizing agents inhibit GABAA ergic function by disrupting the interaction of GABAA receptors with microtubules.
Whatley
V J
VJ
Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262.
Mihic
S J
SJ
Allan
A M
AM
McQuilkin
S J
SJ
Harris
R A
RA
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000502:physiology*; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002417:Cattle; D002712:Chlorides / Q000378:metabolism; D003078:Colchicine / Q000494:pharmacology; D003292:Convulsants / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005445:Flunitrazepam / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008162:Lumicolchicines / Q000378:metabolism; D008566:Membranes / Q000502:physiology; D051379:Mice; D008870:Microtubules / Q000502:physiology*; D009118:Muscimol / Q000494:pharmacology; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D011963:Receptors, GABA-A / Q000502:physiology*; D014747:Vinblastine / Q000494:pharmacology; D014981:Xenopus
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides; D003292:Convulsants; D006657:Histones; D008162:Lumicolchicines; D011963:Receptors, GABA-A; D009118:Muscimol; D014747:Vinblastine; D005445:Flunitrazepam; C037476:tert-butylbicyclophosphorothionate; D017239:Paclitaxel; D015739:Nocodazole; D003078:Colchicine