Colchicine Is a Competitive Antagonist at Human Recombinant g-Aminobutyric AcidA Receptors

نویسنده

  • T. V. DUNWIDDIE
چکیده

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 g-aminobutyric acid (GABA)A receptor function. By use of a rapid drug perfusion system, colchicine (10–1000 mM) significantly inhibited GABA currents recorded from L(tk) cells stably transfected with human a1b2g2L GABAA receptor subunits. The inhibition was rapid and reversible, with 100 mM colchicine shifting the GABA EC50 from 2.5 to 5.1 mM with no effect on currents evoked by saturating concentrations of GABA. Colchicine also significantly inhibited binding of the competitive GABAA receptor antagonist [H]SR-95531. Other microtubule disrupting agents (10 mM vinblastine, 10 mg/ml nocodazole, 1 mM taxol) had no acute effects on GABA currents, nor did the inactive analog g-lumicolchicine (100 mM). 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 GABAA receptor function through a direct interaction with the receptor/ion channel complex. Colchicine is a plant-derived alkaloid that binds to tubulin and depolymerizes microtubules (Osborn and Weber, 1976; Walker and Whitfield, 1985), disrupts axonal transport (Karlsson and Sjostrand, 1969; Fink et al., 1973; Wooten et al., 1975) and inhibits mitosis (Wilson and Friedkin, 1966, 1967; Wang et al., 1975). This compound has been used clinically in the treatment of gout (Hastie, 1991) and has also been used extensively as an experimental tool to characterize cellular processes that involve microtubule structure and axoplasmic transport (Chiaia et al., 1996; Schmalz et al., 1996; Tandon et al., 1996; Saib et al., 1997). Numerous studies have also used colchicine as a neurotoxin to cause lesions in discrete brain regions, such as the dentate gyrus (Brady et al., 1992; Newell et al., 1993; Tandon et al., 1994; Gobbi et al., 1996) and the septum (Peterson and McGinty, 1988; Gilbert and Peterson, 1991), and several recent studies have suggested that colchicine neurotoxicity may model some of the neuropathological aspects of Alzheimer’s dementia (Nakagawa et al., 1987; Mattson, 1992). In all of these cases, the mechanism of colchicine action has been attributed to its inhibition of tubulin binding and subsequent disruption of processes that depend on the integrity of cytoskeletal architecture. However, the mechanism(s) underlying these diverse actions of colchicine have not been determined experimen-

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Colchicine is a competitive antagonist at human recombinant gamma-aminobutyric acidA receptors.

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 t...

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تاریخ انتشار 1997