Voltage-gated Nav channel targeting in the heart requires an ankyrin-G dependent cellular pathway. J Cell Biol 2008 Jan 14;180(1):173-86
Date
01/09/2008Pubmed ID
18180363Pubmed Central ID
PMC2213608DOI
10.1083/jcb.200710107Scopus ID
2-s2.0-38349080944 (requires institutional sign-in at Scopus site) 144 CitationsAbstract
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.
Author List
Lowe JS, Palygin O, Bhasin N, Hund TJ, Boyden PA, Shibata E, Anderson ME, Mohler PJMESH terms used to index this publication - Major topics in bold
AnimalsAnkyrins
Base Sequence
Cells, Cultured
Humans
Ion Channel Gating
Models, Molecular
Molecular Sequence Data
Muscle Proteins
Myocytes, Cardiac
NAV1.5 Voltage-Gated Sodium Channel
Protein Interaction Mapping
Protein Structure, Tertiary
RNA Interference
Rats
Sodium Channels
Transduction, Genetic
