Cytoskeletal Protein 4.1R Affects Repolarization and Regulates Calcium Handling in the Heart

Stagg, Mark A. and Carter, Edward and Sohrabi, Nadia and Siedlecka, Urszula and Soppa, Gopal K. and Mead, Fiona and Mohandas, Narla and Taylor-Harris, Pamela M. and Baines, Anthony J. and Bennett, Pauline M. and Yacoub, Magdi H. and Pinder, Jennifer C. and Terracciano, Cesare M.N. (2008) Cytoskeletal Protein 4.1R Affects Repolarization and Regulates Calcium Handling in the Heart. Circulation Research, 103 (8). 855-U177. ISSN 0009-7330 . (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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The 4.1 proteins are a family of multifunctional adaptor proteins. They promote the mechanical stability of plasma membranes by interaction with the cytoskeletal proteins spectrin and actin and are required for the cell surface expression of a number of transmembrane proteins. Protein 4.1R is expressed in heart and upregulated in deteriorating human heart failure, but its functional role in myocardium is unknown. To investigate the role of protein 4.1R on myocardial contractility and electrophysiology, we studied 4.1R-deficient (knockout) mice (4.1R KO). ECG analysis revealed reduced heart rate with prolonged Q-T interval in 4.1R KO. No changes in ejection fraction and fractional shortening, assessed by echocardiography, were found. The action potential duration in isolated ventricular myocytes was prolonged in 4.1R KO. Ca2+ transients were larger and slower to decay in 4.1R KO. The sarcoplasmic reticulum Ca2+ content and Ca2+ sparks frequency were increased. The Na+/Ca2+ exchanger current density was reduced in 4.1R KO. The transient inward current inactivation was faster and the persistent Na+ current density was increased in the 4.1R KO group, with possible effects on action potential duration. Although no major morphological changes were noted, 4.1R KO hearts showed reduced expression of NaV1.5{alpha} and increased expression of protein 4.1G. Our data indicate an unexpected and novel role for the cytoskeletal protein 4.1R in modulating the functional properties of several cardiac ion transporters with consequences on cardiac electrophysiology and with possible significant roles during normal cardiac function and disease.

Item Type: Article
Uncontrolled keywords: cardiac cytoskeleton; ion transporter regulation; EC coupling
Subjects: Q Science > QP Physiology (Living systems)
Divisions: Faculties > Science Technology and Medical Studies > School of Biosciences
Depositing User: Anthony Baines
Date Deposited: 11 Sep 2009 10:23
Last Modified: 09 Jun 2014 15:53
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