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Abstract
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 language | English |
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Article number | e2207887120 |
Number of pages | 12 |
Journal | Proceedings of the National Academy of Sciences |
Volume | 120 |
Issue number | 7 |
Early online date | 6 Feb 2023 |
DOIs | |
Publication status | Published - 14 Feb 2023 |
Keywords
- acylation
- excitation–contraction coupling
- heart
- ion transport
ASJC Scopus subject areas
- General
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Dive into the research topics of 'Palmitoylation of the pore-forming subunit of Ca(v)1.2 controls channel voltage sensitivity and calcium transients in cardiac myocytes'. Together they form a unique fingerprint.Projects
- 2 Finished
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The Role of NCX1 Palmitoylation in Cardiac Function
Ashford, M. (Investigator) & Fuller, W. (Investigator)
25/09/17 → 24/09/21
Project: Research
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Palmitoylation of the L-Type Ca Channel Pore-Forming Subunit (joint with University of Bristol)
Fuller, W. (Investigator) & Hales, T. (Investigator)
29/08/16 → 27/02/18
Project: Research