The dispensability of 14-3-3 proteins for the regulation of human cardiac sodium channel Na_v1.5

Background 14-3-3 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 Na(v)1.5. Given the many cardiac arrhythmias associated with Na(v)1.5 dysfunction, understanding its regulation by the protein partners is crucial. Aims In this study, we aimed to investigate the role of 14-3-3 proteins in the regulation of the human cardiac sodium channel Na(v)1.5. Methods and results Amongst the seven 14-3-3 isoforms, only 14-3-3 eta (encoded by YWHAH gene) weakly co-immunoprecipitated with Na(v)1.5 when heterologously co-expressed in tsA201 cells. Total and cell surface expression of Na(v)1.5 was however not modified by 14-3-3 eta overexpression or inhibition with difopein, and 14-3-3 eta did not affect physical interaction between Na(v)1.5 alpha-alpha subunits. The current-voltage relationship and the amplitude of Na(v)1.5-mediated sodium peak current density were also not changed. Conclusions Our findings illustrate that the direct implication of 14-3-3 proteins in regulating Na(v)1.5 is not evident in a transformed human kidney cell line tsA201.