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Vol. 60, Issue 5, 1121-1132, November 2001
Department of Pharmacology, University of Virginia,
Charlottesville, Virginia (J.C.G., E.P.-R.)
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: 
1G, 1H, and 1I. 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,
-methyl--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: KI for 1G and 1I
was 0.3 to 0.5 mM and for 1H 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.
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