Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes
- 3 December 2004
- journal article
- Published by National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 101 (50) , 17533-17538
Abstract
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 Navchannels at sites of function in multiple excitable cell types.Keywords
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