Proteomic and functional mapping of cardiac Na V 1.5 channel phosphorylation reveals multisite regulation of surface expression and gating - Archive ouverte HAL Accéder directement au contenu
Pré-Publication, Document De Travail Année : 2020

Proteomic and functional mapping of cardiac Na V 1.5 channel phosphorylation reveals multisite regulation of surface expression and gating

Emily Wagner
  • Fonction : Auteur
Dan Maloney
  • Fonction : Auteur
Kiersten Ruff
  • Fonction : Auteur
Rohit Pappu
Stefan Wagner
  • Fonction : Auteur
Jeanne Nerbonne
  • Fonction : Auteur
Jonathan Silva
  • Fonction : Auteur
R. Reid Townsend
  • Fonction : Auteur
Lars Maier
  • Fonction : Auteur
Céline Marionneau

Résumé

Phosphorylation of Na V 1.5 channels regulates cardiac excitability, yet the phosphorylation sites regulating channel function and the underlying mechanisms remain largely unknown. Using a systematic quantitative phosphoproteomic approach, we analyzed Na V 1.5 channel complexes purified from non-failing 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-664 and -667 regulate the voltage-dependence of channel activation in a cumulative manner, whereas phosphorylation of the nearby serine-671, which is increased in failing hearts, decreases 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, the results demonstrate that ventricular Na V 1.5 is highly phosphorylated, and that the phosphorylation-dependent regulation of Na V 1.5-encoded channels is highly complex, site-specific and dynamic.

Dates et versions

hal-02999198 , version 1 (10-11-2020)

Identifiants

Citer

Maxime Lorenzini, Sophie Burel, Adrien Lesage, Emily Wagner, Camille Charrière, et al.. Proteomic and functional mapping of cardiac Na V 1.5 channel phosphorylation reveals multisite regulation of surface expression and gating. 2020. ⟨hal-02999198⟩
32 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More