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

Babu, Gopal J.; Bhupathy, Poornima; Petrashevskaya, Natalia; Wang, Honglan; Raman, Sripriya; Wheeler, Debra G.; Jagatheesan, Ganapathy; Wieczorek, David; Schwartz, Arnold; Janssen, Paul M. L.; Ziolo, Mark T.; Periasamy, Muthu

doi:10.1074/jbc.m508998200

Cited by 66 publications

(86 citation statements)

References 31 publications

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“…Both PLB and SLN inhibit SERCA activity in the heart by lowering the apparent calcium affinity of the pump [42,46,47]. The inhibitory effect of SLN is relieved upon β-adrenergic stimulation, as observed for PLB [13,[46][47][48]. Although, PLB and SLN inhibit SERCA2a activity, there might be subtle but important differences in their mechanism of regulation.…”

Section: Sln Functionally Differs From Plbmentioning

confidence: 94%

“…Although, PLB and SLN inhibit SERCA2a activity, there might be subtle but important differences in their mechanism of regulation. For example, as illustrated in Figure 3, the inhibitory effect of PLB on SERCA2a is relieved at high calcium concentrations [42], whereas the inhibitory effect of SLN on SERCA2a is observed even at high calcium [46,47]. These functional differences could be attributed to the structural differences in the lumenal domains (C-terminus) of the two proteins.…”

Section: Sln Functionally Differs From Plbmentioning

confidence: 99%

“…Our lab used the cardiac specific α-MHC promoter to overexpress mouse SLN in the atria and ventricles [47]. To study the role of SLN, the SLN: SERCA2a ratio was increased in the ventricle, where the level of SLN is naturally low.…”

Section: Transgenic Approaches To Study the Role Of Plb And Sln In Camentioning

confidence: 99%

“…The available data suggests that SLN and PLB independently regulate SERCA2a activity [16,20,[46][47][48]. Both PLB and SLN inhibit SERCA activity in the heart by lowering the apparent calcium affinity of the pump [42,46,47].…”

Section: Sln Functionally Differs From Plbmentioning

confidence: 99%

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Sarcolipin and phospholamban as regulators of cardiac sarcoplasmic reticulum Ca2+ ATPase

Bhupathy¹,

Babu²,

Periasamy³

2007

Journal of Molecular and Cellular Cardiology

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119

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The cardiac sarcoplasmic reticulum calcium ATPase (SERCA2a) plays a critical role in maintaining the intracellular calcium homeostasis during cardiac contraction and relaxation. It has been well documented over the years that altered expression and activity of SERCA2a can lead to systolic and diastolic dysfunction. The activity of SERCA2a is regulated by two structurally similar proteins, phospholamban (PLB) and sarcolipin (SLN). Although, the relevance of PLB has been extensively studied over the years, the role SLN in cardiac physiology is an emerging field of study. This review focuses on the advances in the understanding of the regulation of SERCA2a by SLN and PLB. In particular, it highlights the similarities and differences between the two proteins and their roles in cardiac patho-physiology.

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Section: Sln Functionally Differs From Plbmentioning

confidence: 94%

Section: Sln Functionally Differs From Plbmentioning

confidence: 99%

Section: Transgenic Approaches To Study the Role Of Plb And Sln In Camentioning

confidence: 99%

Section: Sln Functionally Differs From Plbmentioning

confidence: 99%

See 2 more Smart Citations

Sarcolipin and phospholamban as regulators of cardiac sarcoplasmic reticulum Ca2+ ATPase

Bhupathy¹,

Babu²,

Periasamy³

2007

Journal of Molecular and Cellular Cardiology

Self Cite

119

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“…Recently, however, the role of SLN in cardiac physiology was investigated using transgenic mouse models (11,12). Specifically, it was found that the overexpression of SLN affects calcium transport on the sarco(endo)plasmic reticulum, decreasing the amplitude of the calcium transient and the rate of muscle relaxation (11).…”

mentioning

confidence: 99%

Two-Dimensional Solid-State NMR Reveals Two Topologies of Sarcolipin in Oriented Lipid Bilayers

et al. 2006

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Sarcolipin (SLN), a 31 amino acid integral membrane protein, regulates SERCA1a and SERCA2a, two isoforms of the sarco(endo)plasmic Ca-ATPase, by lowering their apparent Ca 2+ affinity and thereby enabling muscle relaxation. SLN is expressed in both fast-twitch and slow-twitch muscle fibers with significant expression levels also found in the cardiac muscle. SLN shares ∼30% identity with the transmembrane domain of phospholamban (PLN), and recent solution NMR studies carried out in detergent micelles indicate that the two polypeptides bind to SERCA in a similar manner. Previous 1D solid-state NMR experiments on selectively 15 N-labeled sites showed that SLN crosses the lipid bilayer with an orientation nearly parallel to the bilayer normal. With a view toward the characterization of SLN structure and its interactions with both lipids and SERCA, herein we report our initial structural and topological assignments of SLN in mechanically oriented DOPC/DOPE lipid bilayers as mapped by 2D 15 N PISEMA experiments. The PISEMA spectra obtained on uniformly 15 N-labeled protein as well as 15 N-Leu, 15 N-Ile and 15 N-Val map the secondary structure of SLN and, simultaneously, reveal that SLN exists in two distinct topologies. Both the major and the minor populations assume an orientation with the helix axis tilted by ∼23°with respect to the lipid bilayer normal, but vary in the rotation angle about the helix axis by ∼5°. The existence of the multiple populations in model membranes may be a significant requirement for SLN interaction with SERCA.The integral membrane protein sarcolipin (SLN) is expressed in both fast-twitch and slow-twitch muscle fibers. Recently, significant expression levels of SLN have been identified in cardiac muscle, increasing interest in this protein.In rats and mice, SLN expression is restricted to the heart and skeletal muscle, whereas in humans and rabbits, a different expression pattern is observed (1-4). The different localization pattern amongst species has been attributed to sequence variations in the N-terminal and/or transmembrane residues of SLN. MacLennan and co-workers found that the highly conserved C-terminal tail (RSYQY) of SLN is responsible for the localization of SLN in the endoplasmic reticulum (5).The specific role of SLN in the regulation of heart muscle has yet to be fully understood. One hypothesis is that SLN increases the rate of the leakage of Ca 2+ into the lumen, augmenting ATP hydrolysis mediated heat production (6, 7). A second hypothesis is that SLN physically interacts with SERCA2a in tandem with phospholamban (PLN), its functional homolog, constituting a superinhibitory complex (8).In support of the latter hypothesis, in vivo and in vitro experiments show that SLN alone lowers SERCA's apparent Ca 2+ affinity in a manner similar to that by PLN (9), whereas the simultaneous reconstitution of SLN and PLN produces a superinhibitory effect on SERCA (8).Initially, no posttranslational modifications were identified in SLN co-purified with SERCA (10), leading to the ...

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Gene Therapy for Cardiovascular Disease: Inserting New Genes, Regulating the Expression of Native Genes, and Correcting Genetic Defects

Jovin¹,

Giordano²

2007

Cardiovascular Genetics and Genomics for the Cardiologist

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

Cited by 66 publications

References 31 publications

Sarcolipin and phospholamban as regulators of cardiac sarcoplasmic reticulum Ca2+ ATPase

Sarcolipin and phospholamban as regulators of cardiac sarcoplasmic reticulum Ca2+ ATPase

Two-Dimensional Solid-State NMR Reveals Two Topologies of Sarcolipin in Oriented Lipid Bilayers

Gene Therapy for Cardiovascular Disease: Inserting New Genes, Regulating the Expression of Native Genes, and Correcting Genetic Defects

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