SERCA isoforms

Paul There are two SERCA isoforms in smooth muscle, 2A and 2B, in roughly equal proportions. We suspect that there is a reason for this for example, one may be the housekeeping isoform found all over the place. 

Raeymaekers Ie. don t have any data on this. We didn t look at SERCA isoforms in endothelial cells. It is an interesting question though. 

Table 1. Human ATP2A1-3 genes, SERCA isoforms, tissue expression and disease...

SERCA2a is expressed predominantly in the heart, in slow twitch skeletal muscle and in the brain, where it represents the main SERCA isoform. In contrast, SERCA2b is a house-keeping isoform, ubiquitously expressed in smooth muscle and non-muscle tissue (Wuytack et al., 2002). Although both isoforms are detectable in keratinocytes and dermal fibroblasts in culture, SERCA2b is the major isoform expressed in the epidermis from adult skin sections. SERCA2c is expressed in epithelial, mesenchymal and hematopoietic cell lines, and in monocytes (Table 1). 

Figure 1. Alternatively splicing of human ATP2A1-3 genes generates multiple SERCA isoforms. Exons are represented by open boxes, introns by horizontal lines. The different splicings are indicated by lines and letters and are described in the text. Sa-Se indicate the position of stop codons of the different isoforms. Boxes in grey represent coding sequences specific for the isoforms...

SERCA1 and SERCA2a The enzymatic properties of SERCA isoforms... 

In muscle cells, the contraction is induced by Ca2+ release from the sarcoplasmic reticulum, as a result of membrane depolarization and activation of RyRl receptors located at the surface of the SR. The subsequent transport of cytoplasmic Ca2+ back into the lumen of the sarcoplasmic reticulum restores low resting calcium levels and allows muscle relaxation. In fast-twitch skeletal muscle fibers, Ca2+ uptake is mediated by the sarco(endo)plasmic reticulum Ca2+ ATPase SERCA1 which represents more than 99% of SERCA isoforms in these muscle fibers. 

Table 5. Characteristics of Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA) Isoforms and Tissue Distribution of Isoform mRNAs...

There are at least five distinct isoforms of plasma membrane Ca -ATPases in mammalian tissues that differ in distribution and C-terminal sequences [34]. The molecular weight of these enzymes is in the range of 127 300-134683 (Table I) and they all contain calmodulin-binding domains [3], in contrast to the much smaller ( 110kDa) SERCA enzymes that are calmodulin independent. 

The smooth endoplasmic reticulum calcium pumps (SERCA) found in brain were first identified in sarcoplasmic reticulum. The three isoforms of SERCA are products of separate genes SERCA-1 is expressed in fast-twitch skeletal muscle SERCA-2a in cardiac/slow-twitch muscle SERCA-2b, an alternatively spliced form, is expressed in smooth muscle and non-muscle tissues SERCA-3 is... 

The uniquely high resolution structural data available for the SERCAIa Ca2+ pump illuminates the structure of all P-type transporters. Unlike the Na,K pump, the catalytic subunit of the SERCA Ca2+ pumps is active and does not require association with another subunit. However, the cardiac isoform, SERCA-2a, associates with a small membrane protein, phospholamban, that can... 

Paul We have been talking about the SR as a site of release, as if it were one thing. There is superficial SR, deep SR and ER, with three different ryanodine receptor isoforms and at least two different SERCAs. Are these on the same vesicles, or different vesicles What s the role of the ER Do they communicate with one another There are a lot of questions about this compartmentalization and vectorial release. The mitochondria also intrigue me the SR can still function quite well after CCCP (carbonyl cyanide ///-chlorophenylhydrazone), which inhibits mitochondrial Ca2+ uptake. 

Ca2+ is pumped into the SR stores by specific ATPases, the SERCA pumps. Three SERCA genes have been identified and several alternatively spliced gene products. In muscles SERCA1 is predominantly expressed in fast-twitch striated muscles and SERCA 2 isoforms are dominant in slow twitch, heart and smooth muscles, with SERCA2a in the former two, and SERCA2b predominant in smooth muscle and non-muscle cells. SERCA3 has a widespread distribution. 

In humans, SERCA pumps are encoded by three genes, ATP2A1-3, each encoding several protein isoforms (SERCAla,b, SERCA2a-c, SERCA3a-f, respectively) as a result of developmental or tissue-specific alternative splicing (Table 1). 

SERCA pumps in cultured COS cells. Their functional properties were studied using isolated microsomes. The initial in vitro studies reported that SERCA1 and SERCA2a isoforms shared similar Ca2+ affinity and velocity of Ca2+ uptake (Vmax). Subsequently, a higher kinetic turnover was demonstrated for the SERCA1 compared with the SERCA2a isoform (5.0- versus 2.6-fold increase in calcium uptake rate) (Sumbilla et al 1999). 

Dode, L., Andersen, J. P., Leshe, N., Dhitavat, J., Vilsen, B., and Hovnanian, A., 2003, Dissection of the functional differences between sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) 1 and 2 isoforms and characterization of Darier disease (SERCA2) mutants by steady-state and transient kinetic analyses. J Biol Chem, 278 47877—89. 

Martin, V., Bredoux, R., Corvazier, E., Van Gorp, R., Kovacs, T., Gelebart, P., and Enouf, J., 2002, Three novel sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) 3 isoforms. Expression, regulation, and function of the membranes of the SERCA3 family. J Biol Chem, 277 24442-52. 

Periasamy, M., and Kalyanasundaram, A., 2007, SERCA pump isoforms Their role in calcium transport and disease. Muscle Nerve. 

Figure 1. Schematic drawing of PMCA. Transmembrane regions are numbered 1—10. Domains defined by the SERCA structure are indicated by differential stippling. Within the A-domain alternative splicing occurs predominant variants are indicated for each isoform (Z, X, Y and W indicate 0, 1, 2 and 3 exons included, respectively). Approximate positions of the phosophoryl-aspartate (D ) and the signature lysine (K) of the nucleotide-binding site are shown. In the C-terminal region, the Ca2+-calmodulin binding site is boxed. Shorter a variants (not shown) at the C splice site have lower Ca2+-calmodulin affinity...

Calcium pumps, also termed Ca +-ATPase, are calcium channels that transport calcium from the low concentration cytoplasm to the high concentration extracellular space or ER/SR lumenal side using the energy of ATP hydrolysis. Based on their locations, calcium pumps are classified into two groups, plasma membrane Ca +-ATPase (PMCA) and sarcoplasmic reticulum Ca +-ATPase (SERCA). " Four basic isoforms of PMCA (PMCAl 4) have been identified and the other PMCA isoforms are the alternative splicing products of the basic isoforms. PMCAl and 4 are ubiquitously expressed in different tissues and PMCA2 and 3 are expressed in nerve cells. Three basic isoforms of SERCA pump and several sphcing variants have also been identified. ... 

The diverse PMCA, SERCA, and NCX isoforms are expressed in a tissue- and development-specific manner, and their apparent redundancy probably enables the cells to select the combination of reactions that exactly meet their specific Ca -signaling requirements. 

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