Inhibition of alpha(1E) Ca(2+) channels by carbonic anhydrase inhibitors

We examined if a range of carbonic anhydrase inhibitors (CAIs) interacted with the high-voltage activated voltage-sensitive calcium channels (VSCCs) encoded by the human alpha(1E) subunit. Whole-cell recordings were made from HEK293 cells stably expressing human alpha(1E)beta(3)-mediated calcium channels. SNX-482 (an alpha(1E) inhibitor) blocked alpha(1E)-mediated VSCCs with an IC(50) close to 10 nM. The anticonvulsant CAI ethoxyzolamide also inhibited these currents, with an IC(50) close to 1 microM, and produced an accompanying 20-mV hyperpolarizing shift in the steady-state inactivation profile. Other structurally diverse CAIs (e.g., acetazolamide and benzolamide) produced approximately 30 - 40% inhibition of alpha(1E)beta(3)-mediated Ca(2+) currents at 10 microM. Topiramate (10 microM), an anticonvulsant with CAI activity, inhibited these currents by 68 +/- 7%. This off-target activity of CAIs at VSCCs may contribute to some of the effects they produce both in vitro and in vivo.