The dispensability of 14-3-3 proteins for the regulation of human cardiac sodium channel Na v 1.5
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Abstract
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 14-3-3η (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 14-3-3η overexpression or inhibition with difopein, and 14-3-3η did not affect physical interaction between Na v 1.5 α-α 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.
Summary
This work shows that only 14-3-3η, exhibits weak/transient interaction with Na v 1.5, and does not modify its total protein expression, plasmalemmal trafficking, and basal biophysical properties of the whole-cell current. Furthermore, inhibition of endogenous 14-3-3/ligand interactions with difopein does not affect the dimerization of Na v 1.5. Therefore, 14-3-3 proteins are suggested to be dispensable for the Na v 1.5 regulation in a heterologous expression system.
