Cell Membrane Expression of Cardiac Sodium Channel Nav1.5 Is Modulated by α-Actinin-2 Interaction

Cardiac sodium channel Nav1.5 plays a critical role in heart excitability and conduction. The molecular mechanism that underlies the expression of Nav1.5 at the cell membrane is poorly understood. Previous studies demonstrated that cytoskeleton proteins can be involved in the regulation of cell surface expression and localization of several ion channels. We performed a yeast two-hybrid screen to identify Nav1.5-associated proteins that may be involved in channel function and expression. We identified α-actinin-2 as an interacting partner of the cytoplasmic loop connecting domains III and IV of Nav1.5 (Nav1.5/LIII−IV). Co-immunoprecipitation and His6 pull-down assays confirmed the physical association between Nav1.5 and α-actinin-2 and showed that the spectrin-like repeat domain is essential for binding of α-actinin-2 to Nav1.5. Patch-clamp studies revealed that the interaction with α-actinin-2 increases sodium channel density without changing their gating properties. Consistent with these findings, coexpr...