This Article Full Text Full Text (PDF) 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 Sweadner, K. J. Search for Related Content PubMed PubMed Citation Articles by Sweadner, K. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL SODIUM Related Collections Related Article

(Circulation Research. 2005;97:510.)
© 2005 American Heart Association, Inc.

Editorials

Phospholemman

A New Force in Cardiac Contractility

Kathleen J. Sweadner

From the Laboratory of Membrane Biology, Massachusetts General Hospital, Boston.

Correspondence to Kathleen J. Sweadner, Laboratory of Membrane Biology, Massachusetts General Hospital, Boston, MA 02114. E-mail sweadner@helix.mgh.harvard.edu

See related article, pages 558–565

Key Words: digitalis • phospholemman • heart failure • Na,K-ATPase

An extract of the first 250 words of the full text is provided, because this article has no abstract.

The control of intracellular Na⁺ levels has long been known to be a crucial part of the regulation of cardiac contractility and the treatment of heart failure. Cardiac glycosides have been used to improve the symptoms of heart failure since William Withering published trials of a foxglove extract obtained from a gypsy woman in the late 1700’s. The active ingredients, digitalis and digoxin, were found to target sodium pump activity in the 1950’s, and the sodium pump was identified as Na,K-ATPase by Nobel Laureate Jens Skou in the 1970’s. Recent studies have established that digitalis does not improve survival in heart failure, but American College of Cardiology/American Heart Association guidelines recommend its use in combination with ACE inhibitors and ß-adrenergic blockade in patients with symptomatic left ventricular systolic dysfunction.

A modest level of inhibition of Na,K-ATPase by digitalis slightly raises cardiac intracellular Na⁺ concentrations, which in turn decreases the driving force for Ca²⁺ extrusion via NCX1, the Na⁺:Ca²⁺ exchanger. In the therapeutic range, the extra cytoplasmic Ca²⁺ will be loaded into the sarcoplasmic reticulum, resulting in normal diastolic Ca²⁺ concentrations but improved systolic Ca²⁺ release, and thus improved contractility. ß-adrenergic stimulation, on the other hand, improves the loading of the sarcoplasmic reticulum (SR) by acting on the Ca²⁺-ATPase, SERCA. ß-adrenergic stimulation improves SR loading by phosphorylating a small regulatory membrane protein, phospholamban, which otherwise acts to reduce the affinity of SERCA for Ca²⁺. The phosphorylation relieves the basal Ca²⁺ ATPase inhibition.

Although the importance of the Na,K-ATPase . . . [Full Text of this Article]

Related Article:

Expression and Phosphorylation of the Na-Pump Regulatory Subunit Phospholemman in Heart Failure

Julie Bossuyt, Xun Ai, J. Randall Moorman, Steven M. Pogwizd, and Donald M. Bers
Circ. Res. 2005 97: 558-565. [Abstract] [Full Text] [PDF]

This article has been cited by other articles:

				C. N. White, E. J. Hamilton, A. Garcia, D. Wang, K. K. M. Chia, G. A. Figtree, and H. H. Rasmussen Opposing effects of coupled and uncoupled NOS activity on the Na+-K+ pump in cardiac myocytes Am J Physiol Cell Physiol, February 1, 2008; 294(2): C572 - C578. [Abstract] [Full Text] [PDF]

				L. Liu and A. Askari beta-Subunit of cardiac Na+-K+-ATPase dictates the concentration of the functional enzyme in caveolae Am J Physiol Cell Physiol, October 1, 2006; 291(4): C569 - C578. [Abstract] [Full Text] [PDF]

				I. Dostanic-Larson, J. N. Lorenz, J. W. Van Huysse, J. C. Neumann, A. E. Moseley, and J. B Lingrel Physiological role of the {alpha}1- and {alpha}2-isoforms of the Na+-K+-ATPase and biological significance of their cardiac glycoside binding site Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R524 - R528. [Abstract] [Full Text] [PDF]