Calmodulin D133H Disrupts Cav1.2 and Kv7.1 Regulation to Prolong Cardiac Action Potentials in Long QT Syndrome
Year: 2025
Type: article
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.
Source: Cells
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
Institutions: University of Liverpool, St Mary's Hospital, Cardiff University
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,258
Awards: Cellular and molecular physiology, G3822517197, A new approach to control aberrant systolic calcium release and associated cardiac arrhythmias, CALM HEART. Investigating the role of calmodulin in cardiac arrhythmia, Regulation of the calcium channel Cav1.2 by calmodulin variants associated with long-QT syndrome, Defining the structural basis of arrhythmia: how do long QT syndrome-associated calmodulin mutations affect Kv7.1?, Signalling In Space And Time: Intracellular Cyclic AMP Dynamics In Human Vascular Smooth Muscle
OpenAlex ID: W4416105185