Published online before print August 11, 2005, doi: 10.1161/01.RES.0000181172.27931.c3
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2005 American Heart Association, Inc.
Cellular Biology |
Expression and Phosphorylation of the Na-Pump Regulatory Subunit Phospholemman in Heart Failure
From the Department of Physiology (J.B., D.M.B.), Loyola University Chicago, Maywood, Ill; Department of Medicine (X.A., S.M.P.), University of Illinois, Chicago; Division of Cardiology (J.R.M.), Department of Internal Medicine, University of Virginia, Charlottesville.
Correspondence to Donald M. Bers, Department of Physiology, Loyola University Chicago, 2160 S First Ave, Maywood, IL 60153. E-mail dbers{at}lumc.edu
Intracellular [Na] is 
3 mmol/L higher in heart failure (HF; in our arrhythmogenic rabbit model;3), and this can profoundly affect cardiac Ca and contractile function via Na/Ca exchange and Na/H exchange. Na/K-ATPase is the primary mechanism of Na extrusion. We examine here in HF rabbits (and human hearts) expression of Na/K-ATPase isoforms and phospholemman (PLM), a putative Na/K-ATPase regulatory subunit that inhibits pump function and is a major cardiac phosphorylation target. Na/K-ATPase 
1- and 2-isoforms were reduced in HF in rabbit ventricular homogenates (by 24%) and isolated myocytes (by 30% and 17%), whereas 3 was increased (50%) in homogenates and decreased (52%) in myocytes (P<0.05). Homogenate Na/K-ATPase activity in left ventricle was also decreased in HF. However, we showed previously that Na/K-ATPase characteristics in intact ventricular myocytes were unaltered in HF. To reconcile these findings, we assessed PLM expression, phosphorylation, and association with Na/K-ATPase. PLM coimmunoprecipitated with Na/K-ATPase 1 and 2 in control and HF rabbit myocytes. PLM expression was reduced in HF by 42% in isolated rabbit left ventricular (LV) myocytes, by 48% in rabbit LV homogenates, and by 24% in human LV homogenate. The fraction of PLM phosphorylated at Ser-68 was increased dramatically in HF. Our results are consistent with a role for PLM analogous to that of phospholamban for SR Ca-ATPase (SERCA): inhibition of Na/K-ATPase function that is relieved on PLM phosphorylation. So reduced Na/K-ATPase expression in HF may be functionally offset by lower inhibition by PLM (because of reduced PLM expression and higher PLM phosphorylation).
Key Words: heart failure • Na/K-ATPase • phospholemman • FXYD proteins
Related Article:
Circ. Res. 2005 97: 510-511.
This article has been cited by other articles:
 |
|
 |
|
  J. Bossuyt, S. Despa, F. Han, Z. Hou, S. L. Robia, J. B. Lingrel, and D. M. Bers Isoform Specificity of the Na/K-ATPase Association and Regulation by Phospholemman J. Biol. Chem., September 25, 2009; 284(39): 26749 - 26757. [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]
|
|
|
|
|
|
X.-Q. Zhang, J. Wang, L. L. Carl, J. Song, B. A. Ahlers, and J. Y. Cheung Phospholemman regulates cardiac Na+/Ca2+ exchanger by interacting with the exchanger's proximal linker domain Am J Physiol Cell Physiol, April 1, 2009; 296(4): C911 - C921. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Murphy and D. A. Eisner Regulation of Intracellular and Mitochondrial Sodium in Health and Disease Circ. Res., February 13, 2009; 104(3): 292 - 303. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. von Lewinski, J. Kockskamper, D. Zhu, H. Post, A. Elgner, and B. Pieske Reduced Stretch-Induced Force Response in Failing Human Myocardium Caused by Impaired Na+-Contraction Coupling Circ Heart Fail, January 1, 2009; 2(1): 47 - 55. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Davis, M. V. Westfall, D. Townsend, M. Blankinship, T. J. Herron, G. Guerrero-Serna, W. Wang, E. Devaney, and J. M. Metzger Designing Heart Performance by Gene Transfer Physiol Rev, October 1, 2008; 88(4): 1567 - 1651. [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]
|
|
|
|
 |
|
 Y. Ikeda, M. Hoshijima, and K. R. Chien Toward Biologically Targeted Therapy of Calcium Cycling Defects in Heart Failure Physiology, February 1, 2008; 23(1): 6 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Y. Cheung Regulation of cardiac contractility: high time for FXYD Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H584 - H585. [Full Text] [PDF]
|
|
|
|
|
|
S. Bibert, S. Roy, D. Schaer, J.-D. Horisberger, and K. Geering Phosphorylation of Phospholemman (FXYD1) by Protein Kinases A and C Modulates Distinct Na,K-ATPase Isozymes J. Biol. Chem., January 4, 2008; 283(1): 476 - 486. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. von Lewinski, E. Bisping, A. Elgner, J. Kockskamper, and B. Pieske Mechanistic insight into the functional and toxic effects of Strophanthidin in the failing human myocardium Eur J Heart Fail, November 1, 2007; 9(11): 1086 - 1094. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Liang, J. Tian, L. Liu, S. Pierre, J. Liu, J. Shapiro, and Z.-J. Xie Identification of a Pool of Non-pumping Na/K-ATPase J. Biol. Chem., April 6, 2007; 282(14): 10585 - 10593. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Arystarkhova, C. Donnet, A. Munoz-Matta, S. C. Specht, and K. J. Sweadner Multiplicity of expression of FXYD proteins in mammalian cells: dynamic exchange of phospholemman and {gamma}-subunit in response to stress Am J Physiol Cell Physiol, March 1, 2007; 292(3): C1179 - C1191. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. G. Berry, S. Despa, W. Fuller, D. M. Bers, and M. J. Shattock Differential distribution and regulation of mouse cardiac Na+/K+-ATPase {alpha}1 and {alpha}2 subunits in T-tubule and surface sarcolemmal membranes Cardiovasc Res, January 1, 2007; 73(1): 92 - 100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Han, J. Bossuyt, S. Despa, A. L. Tucker, and D. M. Bers Phospholemman Phosphorylation Mediates the Protein Kinase C-Dependent Effects on Na+/K+ Pump Function in Cardiac Myocytes Circ. Res., December 8, 2006; 99(12): 1376 - 1383. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Bers Altered Cardiac Myocyte Ca Regulation In Heart Failure. Physiology, December 1, 2006; 21(6): 380 - 387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Bossuyt, S. Despa, J. L. Martin, and D. M. Bers Phospholemman Phosphorylation Alters Its Fluorescence Resonance Energy Transfer with the Na/K-ATPase Pump J. Biol. Chem., October 27, 2006; 281(43): 32765 - 32773. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Lifshitz, M. Lindzen, H. Garty, and S. J. D. Karlish Functional Interactions of Phospholemman (PLM) (FXYD1) with Na+,K+-ATPase: PURIFICATION OF {alpha}1/beta1/PLM COMPLEXES EXPRESSED IN PICHIA PASTORIS J. Biol. Chem., June 9, 2006; 281(23): 15790 - 15799. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-Q. Zhang, B. A. Ahlers, A. L. Tucker, J. Song, J. Wang, J. R. Moorman, J. P. Mounsey, L. L. Carl, L. I. Rothblum, and J. Y. Cheung Phospholemman Inhibition of the Cardiac Na+/Ca2+ Exchanger: ROLE OF PHOSPHORYLATION J. Biol. Chem., March 24, 2006; 281(12): 7784 - 7792. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Sweadner Phospholemman: A New Force in Cardiac Contractility Circ. Res., September 16, 2005; 97(6): 510 - 511. [Full Text] [PDF]
|
|