Disruption of a single copy of the SERCA2 gene results in altered Ca2+ homeostasis and cardiomyocyte function

Yong Ji, M. Jane Lalli, Gopal J. Babu, Yanfang Xu, Darryl L. Kirkpatrick, Lynne H. Liu, Nipavan Chiamvimonvat, Richard A. Walsh, Gary E. Shull, Muthu Periasamy

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103 Scopus citations

Abstract

A mouse model carrying a null mutation in one copy of the sarcoplasmic reticulum (SR) Ca2+-ATPase isoform 2 (SERCA2) gene, in which SERCA2 protein levels are reduced by ~35%, was used to investigate the effects of decreased SERCA2 level on intracellular Ca2+ homeostasis and contractile properties in isolated cardiomyocytes. When compared with wild-type controls, SR Ca2+ stores and Ca2+ release in myocytes of SERCA2 heterozygous mice were decreased by ~40-60% and ~30-40%, respectively, and the rate of myocyte shortening and relengthening were each decreased by ~40%. However, the rate of Ca2+ transient decline (τ) was not altered significantly, suggesting that compensation was occurring in the removal of Ca2+ from the cytosol. Phospholamban, which inhibits SERCA2, was decreased by ~40% in heterozygous hearts, and basal phosphorylation of Ser-16 and Thr-17, which relieves the inhibition, was increased ~2- and 2.1-fold. These results indicate that reduced expression and increased phosphorylatlon of phospholamban provides compensation for decreased SERCA2 protein levels in heterozygous heart. Furthermore, both expression and current density of the sarcolemmal Na+-Ca2+ exchanger were up-regulated. These results demonstrate that a decrease in SERCA2 levels can directly modify intracellular Ca2+ homeostasis and myocyte contractility. However, the resulting deficit is partially compensated by alterations in phospholamban/SERCA2 interactions and by up-regulation of the Na+-Ca2+ exchanger.

Original languageEnglish (US)
Pages (from-to)38073-38080
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number48
DOIs
StatePublished - Dec 1 2000
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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