Calmodulin D133H Disrupts Cav1.2 and Kv7.1 Regulation to Prolong Cardiac Action Potentials in Long QT Syndrome

Highlights What are the main findings? The calmodulin variant D133H disrupts Ca2+-dependent inactivation of Cav1.2 and reduces activation of Kv7.1. D133H reduces Ca2+ affinity and alters interactions with Cav1.2 and Kv7.1 binding domains. What are the implications of the main findings? The dual impact on Cav1.2 and Kv7.1 reveals cross-channel regulatory coupling as a key determinant of ventricular repolarisation. These mechanistic insights broaden understanding of how specific CaM variants remodel cardiac electrical signalling in Long QT syndrome. Abstract Calmodulin (CaM) plays a central role in cardiac excitation–contraction coupling by regulating ion channels, including the L-type calcium (Ca2+) channel Cav1.2 and the voltage-gated potassium (K+) channel Kv7.1. 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 Cav1.2, prolonging Ca2+ influx, while also reducing activation of Kv7.1, 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.

• Publication year

  2025

• Venue

  Cells

• Publication date

  2025-11-01

• Fields of study

  Medicine

• Identifiers
  DOI 10.3390/cells14221763PMID 41294816PMCID 12651261
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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