Targeted Overexpression of Sarcolipin in the Mouse Heart Decreases Sarcoplasmic Reticulum Calcium Transport and Cardiac Contractility

The role of sarcolipin (SLN) in cardiac physiology was critically evaluated by generating a transgenic (TG) mouse model in which the SLN to sarco(endoplasmic)reticulum (SR) Ca2+ ATPase (SERCA) ratio was increased in the ventricle. Overexpression of SLN decreases SR calcium transport function and res...

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Published in:The Journal of biological chemistry 2006-02, Vol.281 (7), p.3972-3979
Main Authors: Babu, Gopal J., Bhupathy, Poornima, Petrashevskaya, Natalia N., Wang, Honglan, Raman, Sripriya, Wheeler, Debra, Jagatheesan, Ganapathy, Wieczorek, David, Schwartz, Arnold, Janssen, Paul M.L., Ziolo, Mark T., Periasamy, Muthu
Format: Article
Language:English
Subjects:
Animals
Biological Transport
Calcium - metabolism
Calcium-Binding Proteins - metabolism
Calcium-Transporting ATPases - physiology
Isoproterenol - pharmacology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Muscle Proteins - physiology
Myocardial Contraction
Myocardium - metabolism
Phosphorylation
Proteolipids - physiology
Sarcoplasmic Reticulum - metabolism
Sarcoplasmic Reticulum Calcium-Transporting ATPases
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Summary:The role of sarcolipin (SLN) in cardiac physiology was critically evaluated by generating a transgenic (TG) mouse model in which the SLN to sarco(endoplasmic)reticulum (SR) Ca2+ ATPase (SERCA) ratio was increased in the ventricle. Overexpression of SLN decreases SR calcium transport function and results in decreased calcium transient amplitude and rate of relaxation. SLN TG hearts exhibit a significant decrease in rates of contraction and relaxation when assessed by ex vivo work-performing heart preparations. Similar results were also observed with muscle preparations and myocytes from SLN TG ventricles. Interestingly, the inhibitory effect of SLN was partially relieved upon high dose of isoproterenol treatment and stimulation at high frequency. Biochemical analyses show that an increase in SLN level does not affect PLB levels, monomer to pentamer ratio, or its phosphorylation status. No compensatory changes were seen in the expression of other calcium-handling proteins. These studies suggest that the SLN effect on SERCA pump is direct and is not mediated through increased monomerization of PLB or by a change in PLB phosphorylation status. We conclude that SLN is a novel regulator of SERCA pump activity, and its inhibitory effect can be reversed by β-adrenergic agonists.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M508998200