Post-translational regulation of cardiac Nav1.5 channels

Céline Marionneau

The work developed in this research program focuses on characterizing the regulation of the cardiac Nav1.5 channels by phosphorylation. Following our previous mass spectrometry (MS)-based phosphoproteomic studies that allowed the identification of more than 40 native phosphorylation sites on the mouse ventricular Nav1.5 protein, the next challenge will be (1) to determine the kinases/phosphatases and signaling pathways involved in regulating these sites; (2) to decipher the combinations of sites involved in specific regulations; (3) to characterize the molecular mechanisms underlying these regulations; and (4) to identify the (patho)physiological contexts in which these regulations take place. We will first focus on the role of the protein kinase CK2 (Casein Kinase 2) in targeting Nav1.5 channels to the surface of cardiomyocytes. Our second challenge will investigate the β-adrenergic regulation of the peak and late Na⁺ currents which involves the dual PKA (Protein Kinase A) and CaMKII (Ca²⁺/Calmodulin-dependent protein kinase II) pathway. Finally, we will investigate the role of FHF2 (Fibroblast growth factor Homologous Factor 2) phosphorylation in regulating the inactivation properties of cardiac Nav1.5 channels. The functional investigations of these Nav1.5 post-translational modifications will benefit from the acquisition of an automated high-throughput patch-clamp setup. These analyses will also be extended to human physiology and pathology by examining by MS the status of these post-translational modification sites identified from murine channels in failing versus non-failing human left ventricular tissue samples.
 

Proteomic and functional mapping of cardiac NaV1.5 channel phosphorylation sites. Lorenzini M, Burel S, Lesage A, Wagner E, Charrière C, Chevillard PM, Evrard B, Maloney D, Ruff KM, Pappu RV, Wagner S, Nerbonne JM, Silva JR, Townsend RR, Maier LS, Marionneau C. J Gen Physiol, 2021, 153:e202012646.

C-terminal phosphorylation of NaV1.5 impairs FGF13-dependent regulation of channel inactivation. Burel S, Coyan FC, Lorenzini M, Meyer MR, Lichti CF, Brown JH, Loussouarn G, Charpentier F, Nerbonne JM, Townsend RR, Maier LS, Marionneau C. J Biol Chem 292: 17431–17448, 2017.

Regulation of the cardiac Na+ channel NaV1.5 by post-translational modifications. Marionneau C, Abriel H. J Mol Cell Cardiol 82: 36–47, 2015.

Cardiac Sodium Current Under Sympathetic ControlProtein Phosphatase 2A Regulates Cardiac Na+ Channels. Marionneau C, Abriel H. Circ Res 124: 674–676, 2019.

Voltage-gated sodium channels assemble and gate as dimers. Clatot J, Hoshi M, Wan X, Liu H, Jain A, Shinlapawittayatorn K, Marionneau C, Ficker E, Ha T, Deschênes I. Nat Commun, 2017, 8:2077.

Funding

Our group is currently funded thanks to the following grants:

• NIH grant (2020-2023, R01-HL148803, PI: Jonathan Silva, Washington University in Saint Louis, MO, USA, co-I: Céline Marionneau): Personalizing class I anti-arrhythmic drug therapy
• Grant from the Fondation d’entreprise Genavie (2023, PI: Céline Marionneau): β-adrenergic regulation of cardiac Nav1.5 channels