Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes
PJ Mohler, I Rivolta, C Napolitano… - Proceedings of the …, 2004 - National Acad Sciences
Proceedings of the National Academy of Sciences, 2004•National Acad Sciences
We identify a human mutation (E1053K) in the ankyrin-binding motif of Nav1. 5 that is
associated with Brugada syndrome, a fatal cardiac arrhythmia caused by altered function of
Nav1. 5. The E1053K mutation abolishes binding of Nav1. 5 to ankyrin-G, and also prevents
accumulation of Nav1. 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 Nav1. 5 coimmunoprecipitates with 190-kDa ankyrin-G from detergent-soluble lysates …
associated with Brugada syndrome, a fatal cardiac arrhythmia caused by altered function of
Nav1. 5. The E1053K mutation abolishes binding of Nav1. 5 to ankyrin-G, and also prevents
accumulation of Nav1. 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 Nav1. 5 coimmunoprecipitates with 190-kDa ankyrin-G from detergent-soluble lysates …
We identify a human mutation (E1053K) in the ankyrin-binding motif of Nav1.5 that is associated with Brugada syndrome, a fatal cardiac arrhythmia caused by altered function of Nav1.5. The E1053K mutation abolishes binding of Nav1.5 to ankyrin-G, and also prevents accumulation of Nav1.5 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 Nav1.5 coimmunoprecipitates with 190-kDa ankyrin-G from detergent-soluble lysates from rat heart. These data suggest that Nav1.5 associates with ankyrin-G and that ankyrin-G is required for Nav1.5 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 Nav channels at sites of function in multiple excitable cell types.
National Acad Sciences