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Gomora, JC; Daud, AN; Weiergraber, M; Perez-Reyes, E (2001)


MOL PHARMACOL 60(5):1121-1132
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Inhibition of T-type Ca2+ channels has been proposed to play a role in the therapeutic action of succinimide antiepileptic drugs. Despite the widespread acceptance of this hypothesis, recent studies using rat and cat neurons have failed to confirm inhibition of T-type currents at therapeutically relevant concentrations. The present study re-examines this issue using the three cloned human channels that constitute the T-type family: alpha 1G, alpha 1H, and all. The cloned cDNAs were stably transfected and expressed into mammalian cells, leading to the appearance of typical T-type currents. The results demonstrate that both ethosuximide and the active metabolite of methsuximide, alpha -methyl-alpha -phenylsuccinimide (MPS), block human T-type channels in a state-dependent manner, with higher affinity for inactivated channels. In contrast, succinimide analogs that are not anticonvulsive were relatively poor blockers. The apparent affinity of MPS for inactivated states of the three channels was estimated using two independent measures: K-1 for alpha 1G and alpha 1I was 0.3 to 0.5 mM and for al H was 0.6 to 1.2 mM. T-type channels display current at the end of long pulses (persistent current), and this current was especially sensitive to block (ethosuximide IC50 = 0.6 mM). These drugs also reduced both the size of the T-type window current region and the currents elicited by a mock low threshold spike. We conclude that succinimide antiepileptic drugs are capable of blocking human T-type channels at therapeutically relevant concentrations.