Selective blockade of Ca _v1.2 (α1C) versus Ca _v1.3 (α1D) L-type calcium channels by the black mamba toxin calciseptine

Abstract

L-type voltage-gated calcium channels are involved in multiple physiological functions. Currently available antagonists do not discriminate between L-type channel isoforms. Importantly, no selective blocker is available to dissect the role of L-type isoforms Ca _v1.2 and Ca _v1.3 that are concomitantly co-expressed in the heart, neuroendocrine and neuronal cells. Here we show that calciseptine, a snake toxin purified from mamba venom, selectively blocks Ca _v1.2 -mediated L-type calcium currents (I _CaL) at concentrations leaving Ca _v1.3-mediated I _CaL unaffected in both native cardiac myocytes and HEK-293T cells expressing recombinant Ca _v1.2 and Ca _v1.3 channels. Functionally, calciseptine potently inhibits cardiac contraction without altering the pacemaker activity in sino-atrial node cells, underscoring differential roles of Ca _v1.2− and Ca _v1.3 in cardiac contractility and automaticity. In summary, calciseptine is a selective L-type Ca _v1.2 Ca ²⁺ channel blocker and should be a valuable tool to dissect the role of these L-channel isoforms.

Abstract

L-type voltage-gated calcium channels are involved in multiple physiological functions. Here the authors identify calciseptine, a toxin purified from black mamba venom, as a selective inhibitor of Ca _v1.2 L-type Ca ²⁺ channels.