Voltage-gated Nav channel targeting in the heart requires an ankyrin-G dependent cellular pathway.
Voltage-gated Na(v) channels are required for normal electrical activity in neurons, skeletal muscle, and cardiomyocytes. In the heart, Na(v)1.5 is the predominant Na(v) channel, and Na(v)1.5-dependent activity regulates rapid upstroke of the cardiac action potential. Na(v)1.5 activity requires precise localization at specialized cardiomyocyte membrane domains. However, the molecular mechanisms underlying Na(v) channel trafficking in the heart are unknown. In this paper, we demonstrate that ankyrin-G is required for Na(v)1.5 targeting in the heart. Cardiomyocytes with reduced ankyrin-G display reduced Na(v)1.5 expression, abnormal Na(v)1.5 membrane targeting, and reduced Na(+) channel current density. We define the structural requirements on ankyrin-G for Na(v)1.5 interactions and demonstrate that loss of Na(v)1.5 targeting is caused by the loss of direct Na(v)1.5-ankyrin-G interaction. These data are the first report of a cellular pathway required for Na(v) channel trafficking in the heart and suggest that ankyrin-G is critical for cardiac depolarization and Na(v) channel organization in multiple excitable tissues.
Lowe
John S
JS
Department of Internal Medicine, Division of Cardiology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
Palygin
Oleg
O
Bhasin
Naina
N
Hund
Thomas J
TJ
Boyden
Penelope A
PA
Shibata
Erwin
E
Anderson
Mark E
ME
Mohler
Peter J
PJ
D000818:Animals; D017487:Ankyrins / Q000737:chemistry / Q000378:metabolism*; D001483:Base Sequence; D002478:Cells, Cultured; D006801:Humans; D015640:Ion Channel Gating; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D051381:Rats; D015222:Sodium Channels / Q000737:chemistry / Q000378:metabolism*; D014161:Transduction, Genetic
C490613:ANK3 protein, human; C490614:Ank3 protein, rat; D017487:Ankyrins; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568322:Scn5a protein, rat; D015222:Sodium Channels