title: Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes.
abstract: We identify a human mutation (E1053K) in the ankyrin-binding motif of Na(v)1.5 that is associated with Brugada syndrome, a fatal cardiac arrhythmia caused by altered function of Na(v)1.5. The E1053K mutation abolishes binding of Na(v)1.5 to ankyrin-G, and also prevents accumulation of Na(v)1.5 at cell surface sites in ventricular cardiomyocytes. Ankyrin-G and Na(v)1.5 are both localized at intercalated disc and T-tubule membranes in cardiomyocytes, and Na(v)1.5 coimmunoprecipitates with 190-kDa ankyrin-G from detergent-soluble lysates from rat heart. These data suggest that Na(v)1.5 associates with ankyrin-G and that ankyrin-G is required for Na(v)1.5 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.
authors.affiliation: Howard Hughes Medical Institute and Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA. peter.j.mohler@vanderbilt.edu
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.forename: Ilaria
authors.initials: I
authors.lastname: Rivolta
authors.forename: Carlo
authors.initials: C
authors.lastname: Napolitano
authors.forename: Guy
authors.initials: G
authors.lastname: LeMaillet
authors.forename: Stephen
authors.initials: S
authors.lastname: Lambert
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Priori
authors.forename: Vann
authors.initials: V
authors.lastname: Bennett
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017487:Ankyrins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense / Q000235:genetics*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011485:Protein Binding; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013577:Syndrome
chemical_list: D017487:Ankyrins; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; C568322:Scn5a protein, rat; D015222:Sodium Channels; D018698:Glutamic Acid