title: Targeted overexpression of sarcolipin in the mouse heart decreases sarcoplasmic reticulum calcium transport and cardiac contractility.
abstract: 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.
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University College of Medicine and Public Health, Columbus, 43210, USA.
authors.forename: Gopal J
authors.initials: GJ
authors.lastname: Babu
authors.forename: Poornima
authors.initials: P
authors.lastname: Bhupathy
authors.forename: Natalia N
authors.initials: NN
authors.lastname: Petrashevskaya
authors.forename: Honglan
authors.initials: H
authors.lastname: Wang
authors.forename: Sripriya
authors.initials: S
authors.lastname: Raman
authors.forename: Debra
authors.initials: D
authors.lastname: Wheeler
authors.forename: Ganapathy
authors.initials: G
authors.lastname: Jagatheesan
authors.forename: David
authors.initials: D
authors.lastname: Wieczorek
authors.forename: Arnold
authors.initials: A
authors.lastname: Schwartz
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
authors.forename: Mark T
authors.initials: MT
authors.lastname: Ziolo
authors.forename: Muthu
authors.initials: M
authors.lastname: Periasamy
mesh_terms: 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
chemical_list: 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