Abstract
Alkyl-substituted thiobutyrolactones increase or decrease γ-aminobutyric acidA responses at or near the picrotoxin site, but they are structurally similar to ethosuximide, which prompted us to determine the actions of thiobutyrolactones on voltage-dependent Ca++ currents. We measured Ca++ currents in cultured neonatal rat dorsal root ganglion neurons in the absence and presence of the anticonvulsant α-ethyl,α-methyl-γ-thiobutyrolactone (α-EMTBL) and the convulsant β-ethyl,β-methyl-γ-thiobutyrolactone (β-EMTBL). Low-voltage-activated (T-type) currents were reduced in a concentration-dependent manner, with a maximal reduction of 26% and 30% by α-EMTBL and β-EMTBL, respectively. α-EMTBL reduced high-voltage-activated currents in a concentration- and voltage-dependent manner: maximal responses were 7% when evoked from −80 mV, with more rapid current inactivation; 29% when evoked from −40 mV, with little effect on current inactivation. β-EMTBL increased high-voltage-activated currents ≤20% at 10 to 300 μM, but reduced currents at higher concentrations; the latter action was similar to that of α-EMTBL in its magnitude and voltage dependence. Block of N-type channels with ω-conotoxin GVIA (10 μM) reduced the effect of α-EMTBL and eliminated its voltage dependence. The L-type current component was also reduced by α-EMTBL, with little effect on P- or Q-type current components. The related compound, α-ethyl,α-methyl-γ-butyrolactone, had no effect on Ca++ currents. We conclude that thiobutyrolactones affect voltage-dependent Ca++ currents in a concentration- and voltage-dependent manner, with greater potency on low-voltage-activated channels. Both the ring structure and the position of its alkyl substitutions determine the identity of the targeted Ca++channel subtypes and the manner of regulation.
Footnotes
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Send reprint requests to: Robert A. Gross, M.D., Ph.D., Departments of Neurology and Pharmacology and Physiology, University of Rochester, Box 711, 601 Elmwood Avenue, Rochester, NY 14642.
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↵1 Supported in part by National Institutes of Health grants NS19613 (to R.A.G.) and NS14834 (to D.F.C. and J.A.F.).
- Abbreviations:
- α-EMGBL
- α-ethyl,α-methyl-γ-butyrolactone
- α-EMTBL
- α-ethyl,α-methyl-γ-thiobutyrolactone
- β-EMTBL
- β-ethyl,β-methyl-γ-thiobutyrolactone
- ATP
- adenosine triphosphate
- DRG
- dorsal root ganglion
- GABAA
- γ-aminobutyric acid
- HEPES
- N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
- Received June 3, 1996.
- Accepted October 18, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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