Kuo, C.-W. S. et al. (2023) Palmitoylation of the pore-forming subunit of Ca(v)1.2 controls channel voltage sensitivity and calcium transients in cardiac myocytes. Proceedings of the National Academy of Sciences of the United States of America, 120(7), e220788712. (doi: 10.1073/pnas.2207887120) (PMID:36745790) (PMCID:PMC9963536)
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Abstract
Mammalian voltage-activated L-type Ca2+ channels, such as Ca(v)1.2, control transmem- brane 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 termi- nus 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 palmi- toylated. 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 signifi- cantly 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 Ca 2+ channels in excitable cells.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Dobi, Ms Sara and Fuller, Professor Will and Smith, Professor Godfrey and Kuo, Dr Chien-Wen and Wypijewski, Mr Krzysztof and Da Silva Costa, Dr Ana and Main, Alice and Robertson-Gray, Dr Olivia and MacQuaide, Dr Niall and Gok, Dr Caglar |
| Authors: | Kuo, C.-W. S., Dobi, S., Gök, C., Da Silva Costa, A., Main, A., Robertson-Gray, O., Baptista-Hon, D., Wypijewski, K. J., Costello, H., Hales, T. G., MacQuaide, N., Smith, G. L., and Fuller, W. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
| Journal Name: | Proceedings of the National Academy of Sciences of the United States of America |
| Publisher: | National Academy of Sciences |
| ISSN: | 0027-8424 |
| ISSN (Online): | 1091-6490 |
| Published Online: | 06 February 2023 |
| Copyright Holders: | Copyright © 2023 The Authors |
| First Published: | First published in Proceedings of the National Academy of Sciences of the United States of America 120(7):e2207887120 |
| Publisher Policy: | Reproduced under a Creative Commons licence |
| Data DOI: | 10.5525/gla.researchdata.1352 |
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