Voltage-dependent calcium channels as targets for convulsant and anticonvulsant alkyl-substituted thiobutyrolactones

Robert A. Gross, Douglas F. Covey, James A. Ferrendelli

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15 Scopus citations


Alkyl-substituted thiobutyrolactones increase or decrease γ- aminobutyric acid(A) 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.

Original languageEnglish
Pages (from-to)686-694
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - 1997


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