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) Ca(2+) 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 beta-adrenergic agonists.
Babu
Gopal J
GJ
Department of Physiology and Cell Biology, The Ohio State University College of Medicine and Public Health, Columbus, 43210, USA.
Bhupathy
Poornima
P
Petrashevskaya
Natalia N
NN
Wang
Honglan
H
Raman
Sripriya
S
Wheeler
Debra
D
Jagatheesan
Ganapathy
G
Wieczorek
David
D
Schwartz
Arnold
A
Janssen
Paul M L
PM
Ziolo
Mark T
MT
Periasamy
Muthu
M
D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000502:physiology*; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D011510:Proteolipids / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban
D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D007545:Isoproterenol; D009124:Muscle Proteins; D011510:Proteolipids; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C077258:sarcolipin