Calmodulin D133H Disrupts Ca_v1.2 and K_v7.1 Regulation to Prolong Cardiac Action Potentials in Long QT Syndrome.

Authors

Nitika Gupta, Liam F McCormick, Ella M B Richards, Kirsty Wadmore, Rachael Morris, Vanessa S Morris, Pavel Kirilenko, Ewan D Fowler, Caroline Dart, Nordine Helassa

Published in

Cells. Volume 14. Issue 22. Nov 11, 2025. Epub Nov 11, 2025.

Abstract

Calmodulin (CaM) plays a central role in cardiac excitation-contraction coupling by regulating ion channels, including the L-type calcium (Ca²⁺) channel Ca_v1.2 and the voltage-gated potassium (K⁺) channel K_v7.1. Mutations in CaM are linked to severe arrhythmogenic disorders such as Long QT syndrome (LQTS), yet the molecular mechanisms remain incompletely understood. Here, we investigate the structural and functional consequences of the arrhythmia-associated CaM variant D133H. Biophysical analysis revealed that D133H destabilises Ca²⁺ binding at the C-terminal lobe of CaM, altering its Ca²⁺-dependent conformational changes. Electrophysiological recordings demonstrated that CaM D133H impairs Ca²⁺-dependent inactivation (CDI) of Ca_v1.2, prolonging Ca²⁺ influx, while also reducing activation of K_v7.1, thereby limiting repolarising K⁺ currents. Together, these dual defects converge to prolong action potential duration, providing a mechanistic basis for arrhythmogenesis in LQTS. Our findings establish that CaM D133H perturbs both Ca²⁺ and K⁺ channel regulation, highlighting a shared pathway by which calmodulinopathy mutations disrupt cardiac excitability.

PMID:
41294816
Bibliographic data and abstract were imported from PubMed on 15 Oct 2026.

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