Proteomic and functional mapping of cardiac NaV1.5 channel phosphorylation sites.
Journal
The Journal of general physiology
ISSN: 1540-7748
Titre abrégé: J Gen Physiol
Pays: United States
ID NLM: 2985110R
Informations de publication
Date de publication:
01 02 2021
01 02 2021
Historique:
received:
02
05
2020
revised:
23
10
2020
accepted:
03
12
2020
entrez:
7
1
2021
pubmed:
8
1
2021
medline:
16
10
2021
Statut:
ppublish
Résumé
Phosphorylation of the voltage-gated Na+ (NaV) channel NaV1.5 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 NaV1.5 channel complexes purified from nonfailing and failing mouse left ventricles, and we identified 42 phosphorylation sites on NaV1.5. Most sites are clustered, and three of these clusters are highly phosphorylated. Analyses of phosphosilent and phosphomimetic NaV1.5 mutants revealed the roles of three phosphosites in regulating NaV1.5 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 NaV1.5 expression and peak Na+ current. No additional roles could be assigned to the other clusters of phosphosites. Taken together, our results demonstrate that ventricular NaV1.5 is highly phosphorylated and that the phosphorylation-dependent regulation of NaV1.5 channels is highly complex, site specific, and dynamic.
Identifiants
pubmed: 33410863
pii: 211660
doi: 10.1085/jgp.202012646
pmc: PMC7797897
pii:
doi:
Substances chimiques
NAV1.5 Voltage-Gated Sodium Channel
0
Serine
452VLY9402
Sodium
9NEZ333N27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NINDS NIH HHS
ID : R01 NS056114
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL148803
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL142520
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM103422
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA091842
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000448
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002345
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL034161
Pays : United States
Informations de copyright
© 2021 Lorenzini et al.
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