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(Circulation. 2008;117:1849-1855.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Phospholemman-Mediated Activation of Na/K-ATPase Limits [Na]_i and Inotropic State During β-Adrenergic Stimulation in Mouse Ventricular Myocytes

Sanda Despa, PhD; Amy L. Tucker, MD; Donald M. Bers, PhD

From the Department of Physiology, Loyola University Chicago, Maywood, Ill (S.D., D.M.B.), and Cardiovascular Division, University of Virginia, Charlottesville (A.L.T.).

Correspondence to Donald M. Bers, PhD, Department of Pharmacology, University of California at Davis, Genome Building 3511, Davis, CA 95616-8636. E-mail dmbers{at}ucdavis.edu

Received November 20, 2007; accepted February 8, 2008.

Background— Cardiac Na/K-ATPase (NKA) regulates intracellular Na ([Na]_i), which in turn affects intracellular Ca and thus contractility via Na/Ca exchange. Recent evidence shows that phosphorylation of the NKA-associated small transmembrane protein phospholemman (PLM) mediates β-adrenergic–induced NKA stimulation.

Methods and Results— Here, we tested whether PLM phosphorylation during β-adrenergic activation limits the rise in [Na]_i, Ca transient amplitude, and triggered arrhythmias in mouse ventricular myocytes. In myocytes from wild-type (WT) mice, [Na]_i increased on field stimulation at 2 Hz from 11.1±1.8 mmol/L to a plateau of 15.2±1.5 mmol/L. Isoproterenol induced a decrease in [Na]_i to 12.0±1.2 mmol/L. In PLM knockout (PLM-KO) mice in which β-adrenergic stimulation does not activate NKA, [Na]_i also increased at 2 Hz (from 10.4±1.2 to 17.0±1.5 mmol/L) but was unaltered by isoproterenol. The PLM-mediated decrease in [Na]_i in WT mice could limit the isoproterenol-induced inotropic state. Indeed, the isoproterenol-induced increase in the amplitude of Ca transients was significantly smaller in the WT mice (5.2±0.4- versus 7.1±0.5-fold in PLM-KO mice). This also was the case for the sarcoplasmic reticulum Ca content, which increased by 1.27±0.09-fold in WT mice versus 1.53±0.09-fold in PLM-KO mice. The higher sarcoplasmic reticulum Ca content in PLM-KO versus WT mice was associated with an increased propensity for spontaneous Ca transients and contractions in PLM-KO mice.

Conclusions— These data suggest that PLM phosphorylation and NKA stimulation are an integral part of the sympathetic fight-or-flight response, tempering the rise in [Na]_i and cellular Ca loading and perhaps limiting Ca overload–induced arrhythmias.

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