Vol. 280, Issue 2, 686-694, 1997

Voltage-Dependent Calcium Channels as Targets for Convulsant and Anticonvulsant Alkyl-Substituted Thiobutyrolactones¹

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

Departments of Neurology and Pharmacology and Physiology, University of Rochester, Rochester, New York (R.A.G.), Department of Molecular Biology and Pharmacology, Washington University, St. Louis, Missouri (D.F.C.), and Department of Neurology, University of Texas, Houston, Texas (J.A.F.)

Alkyl-substituted thiobutyrolactones increase or decrease -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 -ethyl,-methyl--thiobutyrolactone (-EMTBL) and the convulsant -ethyl,-methyl--thiobutyrolactone (-EMTBL). Low-voltage-activated (T-type) currents were reduced in a concentration-dependent manner, with a maximal reduction of 26% and 30% by -EMTBL and -EMTBL, respectively. -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. -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 -EMTBL in its magnitude and voltage dependence. Block of N-type channels with -conotoxin GVIA (10 µM) reduced the effect of -EMTBL and eliminated its voltage dependence. The L-type current component was also reduced by -EMTBL, with little effect on P- or Q-type current components. The related compound, -ethyl,-methyl--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.