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J. Biol. Chem., Vol. 283, Issue 46, 31303-31314, November 14, 2008

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Impaired Cardiac Contractility in Mice Lacking Both the AE3 Exchanger and the NKCC1 Na⁺-K⁺-2Cl^– Cotransporter

EFFECTS ON Ca²⁺ HANDLING AND PROTEIN PHOSPHATASES^*

Vikram Prasad, Ilona Bodi¹, Jamie W. Meyer, Yigang Wang^¶, Muhammad Ashraf^¶, Sandra J. Engle, Thomas Doetschman, Karena Sisco^||, Michelle L. Nieman^||, Marian L. Miller^**, John N. Lorenz^||, and Gary E. Shull²

From the Departments of Molecular Genetics, Biochemistry, and Microbiology, ^¶Laboratory Medicine, ^||Molecular and Cellular Physiology, and ^**Environmental Health, Institute of Molecular Pharmacology and Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0524

To analyze the cardiac functions of AE3, we disrupted its gene (Slc4a3) in mice. exchange coupled with Na⁺-dependent acid extrusion can mediate pH-neutral Na⁺ uptake, potentially affecting Ca²⁺ handling via effects on Na⁺/Ca²⁺ exchange. AE3 null mice appeared normal, however, and AE3 ablation had no effect on ischemia-reperfusion injury in isolated hearts or cardiac performance in vivo. The NKCC1 Na⁺-K⁺-2Cl^– cotransporter also mediates Na⁺ uptake, and loss of NKCC1 alone does not impair contractility. To further stress the AE3-deficient myocardium, we combined the AE3 and NKCC1 knock-outs. Double knock-outs had impaired contraction and relaxation both in vivo and in isolated ventricular myocytes. Ca²⁺ transients revealed an apparent increase in Ca²⁺ clearance in double null cells. This was unlikely to result from increased Ca²⁺ sequestration, since the ratio of phosphorylated phospholamban to total phospholamban was sharply reduced in all three mutant hearts. Instead, Na⁺/Ca²⁺ exchanger activity was found to be enhanced in double null cells. Systolic Ca²⁺ was unaltered, however, suggesting more direct effects on the contractile apparatus of double null myocytes. Expression of the catalytic subunit of protein phosphatase 1 was increased in all mutant hearts. There was also a dramatic reversal, between single null and double null hearts, in the carboxymethylation and localization to the myofibrillar fraction, of the catalytic subunit of protein phosphatase 2A, which corresponded to the loss of normal contractility in double null hearts. These data show that AE3 and NKCC1 affect Ca²⁺ handling, PLN regulation, and expression and localization of major cardiac phosphatases and that their combined loss impairs cardiac function.

Received for publication, May 14, 2008 , and in revised form, August 27, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL61974, DK50594, DK57552, HL081859, and HL080686. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by National Institutes of Health Grant T32-HL07382-30.

² To whom correspondence should be addressed: Dept. of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0524. Tel.: 513-558-0056; Fax: 513-558-1885; E-mail: shullge{at}ucmail.uc.edu.

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