Palmitoylation of the pore-forming subunit of Ca(v)1.2 controls channel voltage sensitivity and calcium transients in cardiac myocytes

Significance Proper functioning of the voltage-dependent Ca2+ channel Ca(v)1.2 is indispensable for the normal physiology of smooth, skeletal, and cardiac muscles and for that of neurons and endocrine cells. Here, we report that the pore-forming α1C subunit of Ca(v)1.2 is palmitoylated in cardiac tissue and that this modification controls the voltage sensitivity of Ca(v)1.2 in voltage-clamped engineered cell lines. Ca2+ transients in human induced pluripotent stem cell–derived cardiomyocytes expressing unpalmitoylatable α1C are significantly smaller compared to those in cells expressing wild-type subunits. Targeting the shift in Ca(v)1.2 voltage activation properties caused by α1C palmitoylation could reduce susceptibility to fatal cardiac arrhythmias. Hence, we provide a mechanistic insight into the regulation of this physiologically important cardiac ion channel.

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