Overexpression of sarcolipin decreases myocyte contractility and calcium transient

Babu, Gopal J.; Zheng, Zhuozhao; Natarajan, Poornima; Wheeler, Debra G.; Janssen, Paul M. L.; Periasamy, Muthu

doi:10.1016/j.cardiores.2004.08.012

Cited by 44 publications

(63 citation statements)

References 30 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These changes were associated with increased expression of SERCA2a but not PLN, suggesting that SERCA2a elevations are responsible for the enhanced Ca 2ϩ cycling and contractility in D2-overexpressing mice. However, D2 overexpression also reduced the levels of SLN, which can impair cardiac contractility and depress Ca 2ϩ cycling (26,32) in mouse myocardium as a result of either direct SERCA inhibition or synergistic interaction with PLN to form highly stable ternary SLN͞PLN͞ SERCA2a complexes (24,25). Depressed SLN levels in D2-overexpressing hearts appeared to be TH-dependent, because SLN expression was decreased in hyperthyroid hearts and increased in hypothyroid hearts.…”

Section: Effects Of D2 Expression On Cardiac Function and Ca 2؉ Cyclingmentioning

confidence: 98%

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

Trivieri

Oudit

Sah

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Thyroid hormone (TH) is critical for cardiac development and heart function. In heart disease, TH metabolism is abnormal, and many biochemical and functional alterations mirror hypothyroidism. Although TH therapy has been advocated for treating heart disease, a clear benefit of TH has yet to be established, possibly because of peripheral actions of TH. To assess the potential efficacy of TH in treating heart disease, type 2 deiodinase (D2), which converts the prohormone thyroxine to active triiodothyronine (T3), was expressed transiently in mouse hearts by using the tetracycline transactivator system. Increased cardiac D2 activity led to elevated cardiac T3 levels and to enhanced myocardial contractility, accompanied by increased Ca 2؉ transients and sarcoplasmic reticulum (SR) Ca 2؉ uptake. These phenotypic changes were associated with up-regulation of sarco(endo)plasmic reticulum calcium ATPase (SERCA) 2a expression as well as decreased Na ؉ ͞Ca 2؉ exchanger, ␤-myosin heavy chain, and sarcolipin (SLN) expression. In pressure overload, targeted increases in D2 activity could not block hypertrophy but could completely prevent impaired contractility and SR Ca 2؉ cycling as well as altered expression patterns of SERCA2a, SLN, and other markers of pathological hypertrophy. Our results establish that elevated D2 activity in the heart increases T3 levels and enhances cardiac contractile function while preventing deterioration of cardiac function and altered gene expression after pressure overload.calcium ͉ cardiac hypertrophy ͉ sarcoplasmic reticulum ͉ deiodinase ͉ transgenic mice T hyroid hormone (TH) is essential for normal development in vertebrates (1), with TH levels rising postnatally and peaking in the third week of life (2). This surge is critical for fetal-to-adult switch in the cardiac gene program and is responsible for changes in Ca 2ϩ homeostasis, myosin isozyme content [␣-myosin heavy chain (MHC)-to-␤-MHC switch], and action potential profile (3, 4). Intriguingly, the genetic and functional changes associated with heart failure, such as reduced Ca 2ϩ transients and ␣-MHC-to-␤-MHC shifts, which recapitulate the fetal gene program, are also observed in hypothyroidism (5, 6). In addition, TH metabolism and signaling are abnormal in heart failure (5, 7, 8). For example, circulating and cardiac triiodothyronine (T3) levels (i.e., active TH) are reduced in advanced heart disease, after acute myocardial infarction, and in patients with cardiopulmonary bypass. These T3 changes occur in association with decreased peripheral conversion of thyroxine (T4) into T3 (5, 8) and elevated cardiac deiodinase type 3 (D3) activity (9). TH receptor expression is also altered in pathological hypertrophy (10), and myocardial contractility is impaired in mice lacking TH receptors (11). Not surprisingly, TH and its analogue 3,5-diiodothyropropionic acid (DITPA) have been advocated for treating heart failure (12, 13) and for reversing cardiac dysfunction in patients with hypothyroidism (5), although TH use has been limited by car...

show abstract

Section: Effects Of D2 Expression On Cardiac Function and Ca 2؉ Cyclingmentioning

confidence: 98%

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

Trivieri

Oudit

Sah

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The cytoplasmic domain IA, consisting of residues 1-20, of which the first 16 are likely in an α-helical conformation, cytoplasmic domain IB consisting of residues 21-30 and domain II with residues 31-52 is the hydrophobic transmembrane domain which is probably in an α-helical conformation [13,27,81]. On the other hand, SLN is a 31 amino acid SR membrane protein and shows a distribution pattern similar to SERCA2a and PLB [12,16]. Similar to PLB, the amino acids in SLN are organized into three domains; cytoplasmic domain, transmembrane and lumenal domains.…”

Section: Sarcolipin Is Structurally Similar To Plbmentioning

confidence: 99%

“…On the other hand, SLN levels are predominant in the atria than the ventricle [14][15][16]25]. PLB is also expressed at low levels in slow-twitch skeletal muscles [27,28].…”

Section: Sln and Plb Are Differentially Expressed During Development mentioning

confidence: 99%

See 1 more Smart Citation

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

Bhupathy¹,

Babu²,

Periasamy³

2007

Journal of Molecular and Cellular Cardiology

118

View full text Add to dashboard Cite

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.

show abstract

“…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

View full text Add to dashboard Cite

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 ...

show abstract

Overexpression of sarcolipin decreases myocyte contractility and calcium transient

Abstract: We conclude that SLN may play an important role in regulating the SR calcium ATPase pump, possibly by interacting with phospholamban.

Cited by 44 publications

References 30 publications

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

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

Contact Info

Product

Resources

About