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

Chien-Wen Kuo, Sara Dobi, Ana Costa, Alice Main, Daniel Baptista-Hon, Krzysztof J. Wypijewski, Hannah Costello, Tim G. Hales, Niall MacQuaide, Godfrey L. Smith, William Fuller (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review


Mammalian voltage-activated L-type Ca2+ channels, such as Ca(v)1.2, control transmembrane Ca2+ fluxes in numerous excitable tissues. Here, we report that the pore-forming α1C subunit of Ca(v)1.2 is reversibly palmitoylated in rat, rabbit, and human ventricular myocytes. We map the palmitoylation sites to two regions of the channel: The N terminus and the linker between domains I and II. Whole-cell voltage clamping revealed a rightward shift of the Ca(v)1.2 current-voltage relationship when α1C was not palmitoylated. To examine function, we expressed dihydropyridine-resistant α1C in human induced pluripotent stem cell-derived cardiomyocytes and measured Ca2+ transients in the presence of nifedipine to block the endogenous channels. The transients generated by unpalmitoylatable channels displayed a similar activation time course but significantly reduced amplitude compared to those generated by wild-type channels. We thus conclude that palmitoylation controls the voltage sensitivity of Ca(v)1.2. Given that the identified Ca(v)1.2 palmitoylation sites are also conserved in most Ca(v)1 isoforms, we propose that palmitoylation of the pore-forming α1C subunit provides a means to regulate the voltage sensitivity of voltage-activated Ca2+ channels in excitable cells.

Original languageEnglish
Article numbere2207887120
Number of pages12
JournalProceedings of the National Academy of Sciences
Issue number7
Early online date6 Feb 2023
Publication statusPublished - 14 Feb 2023


  • acylation
  • excitation–contraction coupling
  • heart
  • ion transport

ASJC Scopus subject areas

  • General


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