Role of 14-3-3 proteins in human cardiac sodium channel Nav1.5 regulation

Abstract

AbstractBackground14-3-3 proteins are ubiquitous proteins that play a role in cardiac physiology (e.g., metabolism, development, and cell cycle). Furthermore, 14-3-3 proteins were proposed to regulate the electrical function of the heart by interacting with several cardiac ion channels, including the voltage-gated sodium channel Nav1.5. Given the many cardiac arrhythmias associated with Nav1.5 dysfunction, understanding its regulation by the protein partners is crucial.AimsIn this study, we aimed to investigate the role of 14-3-3 proteins in the regulation of the human cardiac sodium channel Nav1.5.Methods and ResultsAmongst the seven 14-3-3 isoforms, only 14-3-3η (encoded byYWHAH) co-immunoprecipitated with Nav1.5 when heterologously co-expressed in tsA201 cells. Total and cell surface expression of Nav1.5 was however not modified by 14-3-3η overexpression or inhibition with difopein, and 14-3-3η did not affect physical interaction between Nav1.5 α-α subunits. The amplitude of Nav1.5-mediated sodium peak current density significantly increased upon co-expression with difopein.ConclusionsOur findings illustrate that the direct implication of 14-3-3 in regulating Nav1.5 is not evident in the heterologous expression system used here. Potentiation of Nav1.5-mediated current by difopein could be explained by the inhibition of 14-3-3/ligand interactions with other partner proteins of the channel complex (e.g., PKA, PKC, CaMKII) and should be further investigated.