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(Circulation Research. 2001;89:160.)
© 2001 American Heart Association, Inc.

Cellular Biology

Sarcoplasmic Reticulum Ca²⁺ ATPase (SERCA) 1a Structurally Substitutes for SERCA2a in the Cardiac Sarcoplasmic Reticulum and Increases Cardiac Ca²⁺ Handling Capacity

M. Jane Lalli, Ji Yong, Vikram Prasad, Katsuji Hashimoto, Dave Plank, Gopal J. Babu, Darryl Kirkpatrick, Richard A. Walsh, Mark Sussman, Atsuko Yatani, Eduardo Marbán, Muthu Periasamy

From the Division of Cardiology (M.J.L., J.Y., V.P., G.J.B., M.P.), University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Cardiology, Department of Internal Medicine (D.K., R.A.W.), Case Western College of Medicine, Cleveland, Ohio; Division of Molecular Cardiovascular Biology (D.P., M.S.), Children’s Hospital Research Center, Cincinnati, Ohio; Cardiovascular Research Institute (A.Y.), University of Medicine and Dentistry of New Jersey, Hackensack, NJ; and Institute of Molecular Cardiobiology (K.H., E.M.), The Johns Hopkins University, Baltimore, Md. Present affiliation of M.P. is Department of Physiology and Cell Biology, College of Medicine and Public Health, Ohio State University, Columbus, Ohio.

Correspondence to Muthu Periasamy, Department of Physiology and Cell Biology, College of Medicine and Public Health, Ohio State University, 302 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210-1218. E-mail periasamy.1{at}osu.edu

Abstract— Ectopic expression of the sarcoplasmic reticulum (SR) Ca²⁺ ATPase (SERCA) 1a pump in the mouse heart results in a 2.5-fold increase in total SERCA pump level. SERCA1a hearts show increased rates of contraction/relaxation and enhanced Ca²⁺ transients; however, the cellular mechanisms underlying altered Ca²⁺ handling in SERCA1a transgenic (TG) hearts are unknown. In this study, using confocal microscopy, we demonstrate that SERCA1a protein traffics to the cardiac SR and structurally substitutes for the endogenous SERCA2a isoform. SR Ca²⁺ load measurements revealed that TG myocytes have significantly enhanced SR Ca²⁺ load. Confocal line-scan images of field-stimulated SR Ca²⁺ release showed an increased rate of Ca²⁺ removal in TG myocytes. On the other hand, ryanodine receptor binding activity was decreased by 30%. However, TG myocytes had a greater rate of spontaneous ryanodine receptor opening as measured by spark frequency. Whole-cell L-type Ca²⁺ current density was reduced by 50%, whereas the time course of inactivation was unchanged in TG myocytes. These studies provide important evidence that SERCA1a can substitute both structurally and functionally for SERCA2a in the heart and that SERCA1a overexpression can be used to enhance SR Ca²⁺ transport and cardiac contractility.

Key Words: transgenic • contractility • gene therapy • Ca²⁺ load • Ca²⁺ uptake • sparks

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