We identify a human mutation (E1053K) in the ankyrin-binding motif of Na v1.5 that is associated with Brugada syndrome, a fatal cardiac arrhythmia caused by altered function of Na v1.5. The E1053K mutation abolishes binding of Na v1.5 to ankyrin-G, and also prevents accumulation of Na v1.5 at cell surface sites in ventricular cardiomyocytes. Ankyrin-G and Nav1.5 are both localized at intercalated disc and T-tubule membranes in cardiomyocytes, and Na v1.5 coimmunoprecipitates with 190-kDa ankyrin-G from detergent-soluble lysates from rat heart. These data suggest that Na v1.5 associates with ankyrin-G and that ankyrin-G is required for Na v1.5 localization at excitable membranes in cardiomyocytes. Together with previous work in neurons, these results in cardiomyocytes suggest that ankyrin-G participates in a common pathway for localization of voltage-gated Na v channels at sites of function in multiple excitable cell types.arrhythmia ͉ SCN5A ͉ targeting ͉ trafficking ͉ sudden cardiac death
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