Inhibition of α1E Ca2+ Channels by Carbonic Anhydrase Inhibitors

Abstract

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 α1E subunit. Whole-cell recordings were made from HEK293 cells stably expressing human α1Eβ3-mediated calcium channels. SNX-482 (an α1E inhibitor) blocked α1E-mediated VSCCs with an IC50 close to 10 nM. The anticonvulsant CAI ethoxyzolamide also inhibited these currents, with an IC50 close to 1 μM, 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 α1Eβ3-mediated Ca2+ currents at 10 μM. Topiramate (10 μM), 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. Keywords:: voltage-sensitive calcium channel, carbonic anhydrase inhibitor, ethoxyzolamide, human Ca2+ channel subunit α1E, human recombinant