TY - JOUR
T1 - Voltage-dependent calcium channels as targets for convulsant and anticonvulsant alkyl-substituted thiobutyrolactones
AU - Gross, Robert A.
AU - Covey, Douglas F.
AU - Ferrendelli, James A.
PY - 1997
Y1 - 1997
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0030951806&partnerID=8YFLogxK
M3 - Article
C2 - 9023280
AN - SCOPUS:0030951806
SN - 0022-3565
VL - 280
SP - 686
EP - 694
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -