VOLTAGE-DEPENDENT CALCIUM CHANNELS AS TARGETS FOR CONVULSANT AND ANTICONVULSANT ALKYL-SUBSTITUTED THIOBUTYROLACTONES

Alkyl-substituted thiobutyrolactones increase or decrease gamma-aminob utyric acid(A) responses at or near the picrotoxin site, but they are structurally similar to ethosuximide, which prompted us to determine t he actions of thiobutyrolactones on voltage-dependent Ca++ currents. W e measured Ca++ currents in cultured neonatal rat dorsal root ganglion neurons in the absence and presence of the anticonvulsant alpha-ethyl ,alpha-methyl-gamma-thiobutyrolactone (alpha-EMTBL) and the convulsant beta-ethyl,beta-methyl-gamma-thiobutyrolactone (beta-EMTBL). Low-volt age-activated (T-type) currents were reduced in a concentration-depend ent manner, with a maximal reduction of 26% and 30% by alpha-EMTBL and beta-EMTBL, respectively. alpha-EMTBL reduced high-voltage-activated currents in a concentration- and voltage-dependent manner: maximal res ponses were 7% when evoked from -80 mV, with more rapid current inacti vation; 29% when evoked from -40 mV, with little effect on current ina ctivation. beta-EMTBL increased high-voltage-activated currents less t han or equal to 20% at 10 to 300 mu M, but reduced currents at higher concentrations; the latter action was similar to that of alpha-EMTBL i n its magnitude and voltage dependence. Block of N-type channels with omega-conotoxin GVIA (10 mu M) reduced the effect of alpha-EMTBL and e liminated its voltage dependence. The L-type current component was als o reduced by alpha-EMTBL, with little effect on P- or Q-type current c omponents. The related compound, alpha-ethyl,alpha-methyl-gamma-butyro lactone, had no effect on Ca++ currents. We conclude that thiobutyrola ctones affect voltage-dependent Ca++ currents in a concentration- and voltage-dependent manner, with greater potency on low-voltage-activate d channels. Both the ring structure and the position of its alkyl subs titutions determine the identity of the targeted Ca++ channel subtypes and the manner of regulation.