SLN Expression in Cardiac and Skeletal Muscle
Structural Features of SLN
SLN Binding to SERCA Promotes Uncoupling of SERCA from Ca2+ Transport
The mechanism of SLN binding and interaction with SERCA is still an emerging area of research. SLN interaction with SERCA has been recently studied using in vitro functional assays. Studies from Tony Lee’s group first suggested SLN binding to SERCA could promote uncoupling of SERCA ATP hydrolysis from its Ca2+ transport function (Mall et al. 2006). They showed that at saturating protein ratios of SLN/SERCA, SLN did not affect ATP hydrolysis but decreased Ca2+ uptake. Interestingly, the heat released by SERCA is increased in the presence of SLN. Based on this, it was suggested that SLN binding to SERCA prevents the release of Ca2+ into the lumen and promotes slippage of Ca2+ back to the cytosol. The energy released from the resulting ATP hydrolysis would thus be released as heat, without any Ca2+ transport. These initial in vitro studies predicted that SLN could play a role in muscle thermogenesis and temperature homeostasis.
SLN Plays a Role in Muscle Thermogenesis and Metabolism
The physiological relevance of SLN in muscle was studied using genetically manipulated mice (Bal et al. 2012; Maurya et al. 2015). Ablation of SLN does not affect muscle growth and/or function since the WT and null could not be distinguished from each other (Babu et al. 2007a). However, when these SLN ablated mice were challenged with acute cold, they failed to maintain their body temperature, whereas PLB-null mice was able to maintain their body temperature (Bal et al. 2012). Transgenic reintroduction of SLN in the null background restored body temperature (Bal et al. 2012). This confirmed that SLN plays an essential role in muscle thermogenesis. In addition, SLN null mice gained more body weight when challenged with high-fat diet in comparison to WT mice. However, skeletal muscle-specific overexpression of SLN in mice can resist high-fat diet induced obesity and enhanced basal metabolic rate (Maurya et al. 2015). Collectively, these studies have shown that SLN is an important regulator of muscle thermogenesis and basal metabolic rate.
SLN is a 31-aa SR membrane protein, that colocalizes with the SERCA pump. It is primarily expressed in cardiac and skeletal muscle tissues and its expression is regulated in a developmental and tissue-specific manner. SLN binds to the SERCA pump in a Ca2+ sensitive manner but interacts with SERCA even at high Ca2+. Interestingly, SLN binding does not inhibit ATP hydrolysis but promotes uncoupling of SERCA from Ca2+ transport resulting in futile cycling. By this mechanism, SLN can increase ATP hydrolysis and heat production. Current data suggest that SLN plays an important role in muscle thermogenesis and metabolism. These and other studies together suggest that SLN is a novel target to enhance energy expenditure in muscle and control metabolism.
- Asahi M, Sugita Y, Kurzydlowski K, De Leon S, Tada M, Toyoshima C, et al. Sarcolipin regulates sarco (endo) plasmic reticulum Ca2+-ATPase (SERCA) by binding to transmembrane helices alone or in association with phospholamban. Proc Natl Acad Sci USA. 2003;100(9):5040–5.PubMedPubMedCentralCrossRefGoogle Scholar
- Gramolini AO, Kislinger T, Asahi M, Li W, Emili A, MacLennan DH. Sarcolipin retention in the endoplasmic reticulum depends on its C-terminal RSYQY sequence and its interaction with sarco (endo) plasmic Ca2+-ATPases. Proc Natl Acad Sci USA. 2004;101(48):16807–12.PubMedPubMedCentralCrossRefGoogle Scholar
- Maurya SK, Bal NC, Sopariwala DH, Pant M, Rowland LA, Shaikh SA, et al. Sarcolipin is a key determinant of the basal metabolic rate, and its overexpression enhances energy expenditure and resistance against diet-induced obesity. J Biol Chem. 2015;290(17):10840–9.PubMedPubMedCentralCrossRefGoogle Scholar
- Sahoo SK, Shaikh SA, Sopariwala DH, Bal NC, Periasamy M. Sarcolipin protein interaction with sarco (endo) plasmic reticulum Ca2+ ATPase (SERCA) is distinct from phospholamban protein, and only sarcolipin can promote uncoupling of the SERCA pump. J Biol Chem. 2013;288(10):6881–9.PubMedPubMedCentralCrossRefGoogle Scholar