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(Circulation Research. 2008;103:855.)
© 2008 American Heart Association, Inc.

Cellular Biology

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

Mark A. Stagg, Edward Carter, Nadia Sohrabi, Urszula Siedlecka, Gopal K. Soppa, Fiona Mead, Narla Mohandas, Pamela Taylor-Harris, Anthony Baines, Pauline Bennett, Magdi H. Yacoub, Jennifer C. Pinder, Cesare M.N. Terracciano

From the Heart Science Centre (M.A.S., N.S., U.S., G.K.S., F.M., M.H.Y., C.M.N.T.), National Heart & Lung Institute, Imperial College London, United Kingdom; Department of Biosciences (E.C., A.B.), University of Kent, United Kingdom; Red Cell Physiology Laboratory (N.M.), New York Blood Center, New York; and Randall Division of Cell and Molecular Biophysics (P.T.-H., P.B., J.C.P.), King’s College London, United Kingdom.

Correspondence to Dr Cesare M. Terracciano, MD, PhD, Cell Electrophysiology, Heart Science Centre, Imperial College London, NHLI, Harefield Hospital, Harefield, Middlesex, UB9 6JH, UK. E-mail c.terracciano{at}imperial.ac.uk

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 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.

Key Words: cardiac cytoskeleton • ion transporter regulation • EC coupling

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Cardiac Cytoskeleton and Arrhythmia: An Unexpected Role for Protein 4.1R in Cardiac Excitability

Shane R. Cunha and Peter J. Mohler
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