Lorenzini, Maxime and Burel, Sophie and Lesage, Adrien and Wagner, Emily and Charriere, Camille and Chevillard, Pierre-Marie and Evrard, Berangere and Maloney, Dan and Ruff, Kiersten M. and Pappu, Rohit and Wagner, Stefan and Nerbonne, Jeanne M. and Silva, Jonathan R. and Townsend, R. Reid and Maier, Lars S. and Marionneau, Celine (2021) Proteomic and functional mapping of cardiac Na(V)1.5 channel phosphorylation sites. JOURNAL OF GENERAL PHYSIOLOGY, 153 (2): e202012646. ISSN 0022-1295, 1540-7748
Full text not available from this repository. (Request a copy)Abstract
Phosphorylation of the voltage-gated Na+ (Na-V) channel Na(V)1.5 regulates cardiac excitability, yet the phosphorylation sites regulating its function and the underlying mechanisms remain largely unknown. Using a systematic, quantitative phosphoproteomic approach, we analyzed Na(V)1.5 channel complexes purified from nonfailing and failing mouse left ventricles, and we identified 42 phosphorylation sites on Na(V)1.5. Most sites are clustered, and three of these clusters are highly phosphorylated. Analyses of phosphosilent and phosphomimetic Na(V)1.5 mutants revealed the roles of three phosphosites in regulating Na(V)1.5 channel expression and gating. The phosphorylated serines S664 and S667 regulate the voltage dependence of channel activation in a cumulative manner, whereas the nearby S671, the phosphorylation of which is increased in failing hearts, regulates cell surface Na(V)1.5 expression and peak Na' current. No additional roles could be assigned to the other clusters of phosphosites. Taken together, our results demonstrate that ventricular Na(V)1.5 is highly phosphorylated and that the phosphorylation-dependent regulation of Na(V)1.5 channels is highly complex, site specific, and dynamic.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | LATE SODIUM CURRENT; HUMAN HEART-FAILURE; NA+ CHANNEL; VENTRICULAR MYOCYTES; DOWN-REGULATION; EXCITABILITY; MODULATION; CAMKII; MODEL; CONFORMATIONS |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Sep 2022 06:44 |
| Last Modified: | 14 Sep 2022 06:44 |
| URI: | https://pred.uni-regensburg.de/id/eprint/47707 |
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