Inhibition of α_1E 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 α_1E subunit. Whole-cell recordings were made from HEK293 cells stably expressing human α_1Eβ₃-mediated calcium channels. SNX-482 (an α_1E inhibitor) blocked α_1E-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 α_1Eβ₃-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.