RT Journal Article SR Electronic T1 Voltage-Dependent Calcium Channels as Targets for Convulsant and Anticonvulsant Alkyl-Substituted Thiobutyrolactones JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 686 OP 694 VO 280 IS 2 A1 Robert A. Gross A1 Douglas F. Covey A1 James A. Ferrendelli YR 1997 UL http://jpet.aspetjournals.org/content/280/2/686.abstract AB 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. The American Society for Pharmacology and Experimental Therapeutics