Selective blockade of Cav1.2 (α1C) versus Cav1.3 (α1D) L-type calcium channels by the black mamba toxin calciseptine

  • Nat Commun. 2024 Jan 2;15(1):54. doi: 10.1038/s41467-023-43502-w.
Pietro Mesirca  1  2 ,  Jean Chemin  #  3  4 ,  Christian Barrère  #  3  4 ,  Eleonora Torre  3  4 ,  Laura Gallot  3  4 ,  Arnaud Monteil  3  4  5 ,  Isabelle Bidaud  3  4 ,  Sylvie Diochot  4  6 ,  Michel Lazdunski  4  6 ,  Tuck Wah Soong  7 ,  Stéphanie Barrère-Lemaire  3  4 ,  Matteo E Mangoni  3  4 ,  Joël Nargeot  8  9
Affiliations
  • 1. Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, 34094, Montpellier, France. [email protected].
  • 2. Laboratory of Excellence Ion Channels, Science & Therapeutics, F-06560, Valbonne, France. [email protected].
  • 3. Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, 34094, Montpellier, France.
  • 4. Laboratory of Excellence Ion Channels, Science & Therapeutics, F-06560, Valbonne, France.
  • 5. Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
  • 6. Université Côte d'Azur, CNRS, IPMC (Institut de Pharmacologie Moléculaire et Cellulaire), FHU InovPain (Fédération Hospitalo-Universitaire "Innovative Solutions in Refractory Chronic Pain"), F-06560, Valbonne, France.
  • 7. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 8. Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, 34094, Montpellier, France. [email protected].
  • 9. Laboratory of Excellence Ion Channels, Science & Therapeutics, F-06560, Valbonne, France. [email protected].
  • # Contributed equally.
PMID: 38167790 DOI: 10.1038/s41467-023-43502-w
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 CAv1.2 and CAv1.3 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 CAv1.2 -mediated L-type calcium currents (ICaL) at concentrations leaving CAv1.3-mediated ICaL unaffected in both native cardiac myocytes and HEK-293T cells expressing recombinant CAv1.2 and CAv1.3 channels. Functionally, calciseptine potently inhibits cardiac contraction without altering the pacemaker activity in sino-atrial node cells, underscoring differential roles of CAv1.2- and CAv1.3 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.

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