Targeting and stability of Na/Ca exchanger 1 in cardiomyocytes requires direct interaction with the membrane adaptor ankyrin-B.
Na/Ca exchanger activity is important for calcium extrusion from the cardiomyocyte cytosol during repolarization. Animal models exhibiting altered Na/Ca exchanger expression display abnormal cardiac phenotypes. In humans, elevated Na/Ca exchanger expression/activity is linked with pathophysiological conditions including arrhythmia and heart failure. Whereas the molecular mechanisms underlying Na/Ca exchanger biophysical properties are widely studied and generally well characterized, the cellular pathways and molecular partners underlying the specialized membrane localization of Na/Ca exchanger in cardiac tissue are essentially unknown. In this report, we present the first direct evidence for a protein pathway required for Na/Ca exchanger localization and stability in primary cardiomyocytes. We define the minimal structural requirements on ankyrin-B for direct Na/Ca exchanger interactions. Moreover, using ankyrin-B mutants that lack Na/Ca exchanger binding activity, and primary cardiomyocytes with reduced ankyrin-B expression, we demonstrate that direct interaction with the membrane adaptor ankyrin-B is required for the localization and post-translational stability of Na/Ca exchanger 1 in neonatal mouse cardiomyocytes. These results raise exciting new questions regarding potentially dynamic roles for ankyrin proteins in the biogenesis and maintenance of specialized membrane domains in excitable cells.
Cunha
Shane R
SR
Departments of University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.
Bhasin
Naina
N
Departments of University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.
Mohler
Peter J
PJ
Departments of University of Iowa Carver College of Medicine, Iowa City, Iowa 52242; Internal Medicine, Division of Cardiology and University of Iowa Carver College of Medicine, Iowa City, Iowa 52242; Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242. Electronic address: peter-mohler@uiowa.edu.
D000818:Animals; D000831:Animals, Newborn; D017487:Ankyrins / Q000235:genetics / Q000378:metabolism*; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*
C498995:Ank2 protein, mouse; D017487:Ankyrins; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1