Voltage-dependent calcium channels as targets for convulsant and anticonvulsant alkyl-substituted thiobutyrolactones.
Alkyl-substituted thiobutyrolactones increase or decrease gamma-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 alpha-ethyl,alpha-methyl-gamma-thiobutyrolactone (alpha-EMTBL) and the convulsant beta-ethyl,beta-methyl-gamma-thiobutyrolactone (beta-EMTBL). Low-voltage-activated (T-type) currents were reduced in a concentration-dependent 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 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. beta-EMTBL increased high-voltage-activated currents < or = 20% at 10 to 300 microM, but reduced currents at higher concentrations; the latter action was similar to that of alpha-EMTBL in its magnitude and voltage dependence. Block of N-type channels with omega-conotoxin GVIA (10 microM) reduced the effect of alpha-EMTBL and eliminated its voltage dependence. The L-type current component was also reduced by alpha-EMTBL, with little effect on P- or Q-type current components. The related compound, alpha-ethyl,alpha-methyl-gamma-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.
Gross
R A
RA
Department of Neurology, University of Rochester, New York 14642, USA.
Covey
D F
DF
Ferrendelli
J A
JA
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D003292:Convulsants / Q000494:pharmacology*; D005013:Ethosuximide / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects; D005727:Ganglia, Spinal / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley
D000927:Anticonvulsants; D015220:Calcium Channels; D003292:Convulsants; C051894:alpha-ethyl, alpha-methyl-thiobutyrolactone; C051895:beta-ethyl, beta-methyl-thiobutyrolactone; C035544:2-ethyl-2-methyl-4-butyrolactone; D005013:Ethosuximide; D015107:4-Butyrolactone