Selective blockade of Cav₁.2 (1C) versus Ca_v1.3 (1D) L-type calcium channels by the black mamba toxin calciseptine

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 (ICaL) at concentrations leaving Ca(v)1.3mediated ICaL 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 contractionwithout 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 Cav1.2 Ca2+ channel blocker and should be a valuable tool to dissect the role of these L-channel isoforms.