Of the three mammalian members belonging to the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) family, SERCA2 is evolutionary the oldest and shows the most wide tissue-expression pattern. Two major SERCA2 splice variants are well-characterized: the muscle-specific isoform SERCA2a and the housekeeping isoform SERCA2b. Recently, several interacting proteins and post-translational modifications of SERCA2 were identified which may modulate the activity of the Ca2+ pump. This review aims to give an overview of the vast literature concerning the cell biological implications of the SERCA2 isoform diversity and the factors regulating SERCA2. Proteins reported to interact with SERCA2 from the cytosolic domain involve the anti-apoptotic Bcl-2, the insulin receptor substrates IRS1/2, the EF-hand Ca2+-binding protein S100A1 and acylphosphatase. We will focus on the very particular position of SERCA2 as an enzyme functioning in a thin, highly fluid, leaky and cholesterol-poor membrane. Possible differential interactions of SERCA2b and SERCA2a with calreticulin, calnexin and ERp57, which could occur within the lumen of the endoplasmic reticulum will be discussed. Reported post-translational modifications possibly affecting pump activity involve N-glycosylation, glutathionylation and Ca2+/calmodulin kinase II-dependent phosphorylation. Finally, the pronounced vulnerability to oxidative damage of SERCA2 appears to be pivotal in the etiology of various pathologies.
"The long list of putative physical interactors (Usenovic et al., 2012b) points into the direction of ATP13A2 as a scaffolding protein in the regulation of vesicular processes. Like other P-type ATPases, such as the Na + /K + -ATPase (Xie and Xie, 2005) and the SERCA2 Ca 2+ -ATPase (Vangheluwe et al., 2005), ATP13A2 might be acting as a scaffold and exert a transporting function at the same time. Regulation of vesicular processes may include de novo vesicle formation, vesicular transport, vesicular sorting mechanisms and vesicle fusion. "
[Show abstract][Hide abstract] ABSTRACT: Mutations in ATP13A2 lead to Kufor-Rakeb syndrome, a parkinsonism with dementia. ATP13A2 belongs to the P-type transport ATPases, a large family of primary active transporters that exert vital cellular functions. However, the cellular function and transported substrate of ATP13A2 remain unknown. To discuss the role of ATP13A2 in neurodegeneration, we first provide a short description of the architecture and transport mechanism of P-type transport ATPases. Then, we briefly highlight key P-type ATPases involved in neuronal disorders such as the copper transporters ATP7A (Menkes disease), ATP7B (Wilson disease), the Na(+)/K(+)-ATPases ATP1A2 (familial hemiplegic migraine) and ATP1A3 (rapid-onset dystonia parkinsonism). Finally, we review the recent literature of ATP13A2 and discuss ATP13A2's putative cellular function in the light of what is known concerning the functions of other, better-studied P-type ATPases. We critically review the available data concerning the role of ATP13A2 in heavy metal transport and propose a possible alternative hypothesis that ATP13A2 might be a flippase. As a flippase, ATP13A2 may transport an organic molecule, such as a lipid or a peptide, from one membrane leaflet to the other. A flippase might control local lipid dynamics during vesicle formation and membrane fusion events.
"SERCA3 is expressed also in vascular endothelial cells, and expression levels vary according to the proliferative state and the anatomic location of the cells . Several excellent reviews are available about SERCA structure [42,50,55,56,57,58,59], function [35,37,38,39,57,60,61], knock-out animal models [62,63] and genetic diseases [50,64,65,66,67], as well as about the role of calcium signaling in cancer [68,69]. With the aim of attracting attention to the remodeling of ER calcium homeostasis in cancer, we will briefly summarize here available data on the modulation of the expression of SERCA enzymes in several in vitro models of cancer cell differentiation, and on the patterns of SERCA3 protein expression in various human tumors and corresponding normal tissue in situ. "
[Show abstract][Hide abstract] ABSTRACT: The endoplasmic reticulum (ER) is a major intracellular calcium storage pool and a multifunctional organelle that accomplishes several calcium-dependent functions involved in many homeostatic and signaling mechanisms. Calcium is accumulated in the ER by Sarco/Endoplasmic Reticulum Calcium ATPase (SERCA)-type calcium pumps. SERCA activity can determine ER calcium content available for intra-ER functions and for calcium release into the cytosol, and can shape the spatiotemporal characteristics of calcium signals. SERCA function therefore constitutes an important nodal point in the regulation of cellular calcium homeostasis and signaling, and can exert important effects on cell growth, differentiation and survival. In several cell types such as cells of hematopoietic origin, mammary, gastric and colonic epithelium, SERCA2 and SERCA3-type calcium pumps are simultaneously expressed, and SERCA3 expression levels undergo significant changes during cell differentiation, activation or immortalization. In addition, SERCA3 expression is decreased or lost in several tumor types when compared to the corresponding normal tissue. These observations indicate that ER calcium homeostasis is remodeled during cell differentiation, and may present defects due to decreased SERCA3 expression in tumors. Modulation of the state of differentiation of the ER reflected by SERCA3 expression constitutes an interesting new aspect of cell differentiation and tumor biology.
"Of particular relevance is the finding that Sp1 and Sp3 factors regulate SERCA2 transcription in cardiomyocytes (Brady et al. 2003), and that in pressure overload induced CH, Sp1 levels are increased and are partially responsible for regulating decrease in SERCA2 transcription (Takizawa et al. 2003). Although several research groups have investigated the transcriptional regulation of the SERCA2 gene, and there are some reviews about this topic and the diseases associated with the dysregulation of the protein (Vangheluwe et al. 2005; Zarain-Herzberg 2006; Brini and Carafoli 2009), recent reports have highlighted new views of previously unexplored pathways (Fig. 1). Different transcriptional mechanisms are involved in the regulation of SERCA2 gene expression in the heart to maintain calcium homeostasis, in the following sections we review the knowledge of the known participating mechanisms. "
[Show abstract][Hide abstract] ABSTRACT: The precise control of Ca(2+) levels during the contraction-relaxation cycle in cardiac myocytes is extremely important for normal beat-to-beat contractile activity. The sarcoplasmic reticulum (SR) plays a key role controlling calcium concentration in the cytosol. The SR Ca(2+)-ATPase (SERCA2) transports Ca(2+) inside the SR lumen during relaxation of the cardiac myocyte. Calsequestrin (Casq2) is the main protein in the SR lumen, functioning as a Ca(2+) buffer and participating in Ca(2+) release by interacting with the ryanodine receptor 2 (RyR2) Ca(2+)-release channel. Alterations in normal Ca(2+) handling significantly contribute to the contractile dysfunction observed in cardiac hypertrophy and in heart failure. Transcriptional regulation of the SERCA2 gene has been extensively studied and some of the mechanisms regulating its expression have been elucidated. Overexpression of Sp1 factor in cardiac hypertrophy downregulates SERCA2 gene expression and increased levels of thyroid hormone up-regulates its transcription. Other hormones such norepinephrine, angiotensin II, endothelin-1, parathyroid hormone, prostaglandin-F2α, as well the cytokines tumor necrosis factor-α and interleukin-6 also downregulate SERCA2 expression. Calcium acting through the calcineurin-NFAT (nuclear factor of activated T cells) pathway has been suggested to regulate SERCA2 and CASQ2 gene expression. This review focuses on the current knowledge regarding transcriptional regulation of SERCA2 and CASQ2 genes in the normal and pathologic heart.
Canadian Journal of Physiology and Pharmacology 07/2012; 90(8):1017-28. DOI:10.1139/y2012-057 · 1.77 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.