Colchicine is a competitive antagonist at human recombinant gamma -aminobutyric acid sub(A) receptors

• Published in: The Journal of pharmacology and experimental therapeutics 1998-01, Vol.284 (1), p.95-102
• Main Authors: Weiner, J L, Buhler, A V, Whatley, V J, Harris, R A, Dunwiddie, T V
• Format: Article
• Language: English
• ISSN: 0022-3565

Colchicine is an alkaloid that is used clinically in the treatment of arthritic gout. This potent microtubule disrupting agent has also been used extensively as an experimental tool in studies characterizing the role of the cytoskeleton in a variety of cellular processes. Colchicine has also been used as a selective neurotoxin and in animal models of Alzheimer's disease and epilepsy. Although the mechanism(s) mediating the neurotoxic actions of colchicine have not been established, most studies have attributed these effects to its microtubule depolymerizing actions. Here we report another central nervous system action of colchicine, competitive antagonism of gamma -aminobutyric acid (GABA) sub(A) receptor function. By use of a rapid drug perfusion system, colchicine significantly inhibited GABA currents recorded from L(tk super(-)) cells stably transfected with human alpha 1 beta 2 gamma 2L GABA sub(A) receptor subunits. The inhibition was rapid and reversible, with 100 mu M colchicine shifting the GABA EC sub(50) from 2.5 to 5.1 mu M with no effect on currents evoked by saturating concentrations of GABA. Colchicine also significantly inhibited binding of the competitive GABA sub(A) receptor antagonist [ super(3)H]SR-95531. Other microtubule disrupting agents vinblastine, nocodazole, taxol) had no acute effects on GABA currents, nor did the inactive analog gamma -lumicolchicine. Moreover, pretreating cells with colchicine, vinblastine, nocodazole or taxol for 1 to 4 hr did not occlude the acute inhibitory action of colchicine. We conclude that, in addition to its well characterized effects on microtubule assembly, colchicine can also inhibit GABA sub(A) receptor function through a direct interaction with the receptor/ion channel complex.