This Article Full Text Full Text (PDF) All Versions of this Article: 117/14/1849    most recent CIRCULATIONAHA.107.754051v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Despa, S. Articles by Bers, D. M. Search for Related Content PubMed PubMed Citation Articles by Despa, S. Articles by Bers, D. M. Related Collections Calcium cycling/excitation-contraction coupling Ion channels/membrane transport Related Article

(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.

---

 

CLINICAL PERSPECTIVE

Related Article:

Clinical Summaries
Circulation 2008 117: 1769. [Extract] [Full Text]

This article has been cited by other articles:

				J. Wang, T. O. Chan, X.-Q. Zhang, E. Gao, J. Song, W. J. Koch, A. M. Feldman, and J. Y. Cheung Induced overexpression of Na+/Ca2+ exchanger transgene: altered myocyte contractility, [Ca2+]i transients, SR Ca2+ contents, and action potential duration Am J Physiol Heart Circ Physiol, August 1, 2009; 297(2): H590 - H601. [Abstract] [Full Text] [PDF]

				W. Fuller, J. Howie, L. M. McLatchie, R. J. Weber, C. J. Hastie, K. Burness, D. Pavlovic, and M. J. Shattock FXYD1 phosphorylation in vitro and in adult rat cardiac myocytes: threonine 69 is a novel substrate for protein kinase C Am J Physiol Cell Physiol, June 1, 2009; 296(6): C1346 - C1355. [Abstract] [Full Text] [PDF]

				J. Song, X.-Q. Zhang, J. Wang, E. Cheskis, T. O. Chan, A. M. Feldman, A. L. Tucker, and J. Y. Cheung Regulation of cardiac myocyte contractility by phospholemman: Na+/Ca2+ exchange versus Na+-K+-ATPase Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1615 - H1625. [Abstract] [Full Text] [PDF]