Selective blockade of Cav1.2 (α1C) versus Cav1.3 (α1D) L-type calcium channels by the black mamba toxin calciseptine
Pietro Mesirca, Jean Chemin, Christian Barrère, Eleonora Torre, Laura Gallot, Arnaud Monteil, Isabelle Bidaud, Sylvie Diochot, Michel Lazdunski, Tuck Wah Soong, Stéphanie Barrère‐Lemaire, Matteo E. Mangoni, Joël Nargeot
Abstract
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 v 1.2 and Ca v 1.3 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 v 1.2 -mediated L-type calcium currents (I CaL ) at concentrations leaving Ca v 1.3-mediated I CaL unaffected in both native cardiac myocytes and HEK-293T cells expressing recombinant Ca v 1.2 and Ca v 1.3 channels. Functionally, calciseptine potently inhibits cardiac contraction without altering the pacemaker activity in sino-atrial node cells, underscoring differential roles of Ca v 1.2− and Ca v 1.3 in cardiac contractility and automaticity. In summary, calciseptine is a selective L-type Ca v 1.2 Ca 2+ channel blocker and should be a valuable tool to dissect the role of these L-channel isoforms.