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  • Title: Zonisamide block of cloned human T-type voltage-gated calcium channels.
    Author: Matar N, Jin W, Wrubel H, Hescheler J, Schneider T, Weiergräber M.
    Journal: Epilepsy Res; 2009 Feb; 83(2-3):224-34. PubMed ID: 19124225.
    Abstract:
    Zonisamide (ZNS) is a multi-target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures, with T-type Ca(2+) channel blockade being one of its proposed mechanisms of action. In this study, we systematically investigated electrophysiological effects of ZNS on cloned human Ca(v)3.1-3.3 Ca(2+) channels in a heterologous HEK-293 expression system using whole cell patch-clamp technique. Concentration-response studies were performed in the range from 5 microM to 2mM for Ca(v)3.2 Ca(2+) channels exhibiting a 15.4-30.8% reduction of Ca(2+) influx within the maximum therapeutic plasma range (50-200 microM ZNS). The other T-type Ca(2+) channel entities, Ca(v)3.1 and Ca(v)3.3, were even less sensitive to ZNS. Both voltage- and concentration-dependence of inactivation kinetics remained unchanged for Ca(v)3.2 VGCC, whereas Ca(v)3.1 and Ca(v)3.3 exhibited minor, though significant reduction of inactivation-tau. Interestingly, ZNS block of Ca(v)3.2 VGCCs was not use-dependent and remained unaffected by changes in the holding potential. Steady-state inactivation studies did not display a significant shift in steady-state availability of Ca(v)3.2 channels at 100 microM ZNS (DeltaV(1/2)=3.1mV, p=0.071). Our studies indicate that ZNS is a moderate blocker of human Ca(v)3 T-type Ca(2+) channels with little or no effect on Ca(v)3.2 Ca(2+) channel inactivation kinetics, use- and state-dependence of blockade. These results suggest that T-type Ca(2+) channel inhibition only partially contributes to the anti-absence activity of ZNS antiepileptic drug.
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