Disease relevance of Atp2a1

• In contrast to humans, term SERCA1-null mice had progressive cyanosis and gasping respiration and succumbed from respiratory failure shortly after birth [1].
• RESULTS: We demonstrate that reduced expression of SERCA does not lead to cardiac hypertrophy or fibrosis and does not increase resting plasma-norepinephrine levels in HET mice [2].
• Similar increases and decreases in SR Ca(2+)-ATPase protein levels were observed between phospholamban-deficient and wild-type hearts in hyperthyroidism and hypothyroidism, respectively [3].
• There has been considerable controversy over whether a decrease in SERCA level is a cause or effect of hypertrophy [4].
• Adenoviruses expressing a SERCA transgene or a mutant phospholamban transgene exhibiting dominant negative action were used to infect isolated myocytes treated with a phorbol ester (phorbol 12-myristate 13-acetate), which delays the calcium transients [5].

High impact information on Atp2a1

• S-Glutathiolation by peroxynitrite activates SERCA during arterial relaxation by nitric oxide [6].
• Nitric oxide (NO) physiologically stimulates the sarco/endoplasmic reticulum calcium (Ca(2+)) ATPase (SERCA) to decrease intracellular Ca(2+) concentration and relax cardiac, skeletal and vascular smooth muscle [6].
• Purified SERCA was S-glutathiolated by ONOO(-) and the increase in Ca(2+)-uptake activity of SERCA reconstituted in phospholipid vesicles required the presence of glutathione [6].
• Mutation of the SERCA-reactive Cys674 to serine abolished these effects [6].
• Here, we show that NO-derived peroxynitrite (ONOO(-)) directly increases SERCA activity by S-glutathiolation and that this modification of SERCA is blocked by irreversible oxidation of the relevant cysteine thiols during atherosclerosis [6].

Chemical compound and disease context of Atp2a1

• The absence of SERCA1 in type II fibers, and the absence of compensatory increases in other Ca(2+) handling proteins, coupled with the marked increase in contractile function required of the diaphragm muscle to support postnatal respiration, can account for respiratory failure in term SERCA1-null mice [1].

Biological context of Atp2a1

• The gene encoding sarcoplasmic reticulum calcium ATPase-1 (Atp2a1) maps to distal mouse chromosome 7 [7].
• Phenotypes of SERCA and PMCA knockout mice [8].
• PLB inhibits the SR Ca(2+)-ATPase in cardiac muscle; this inhibition is relieved on phosphorylation [9].
• The percentage of affected homozygote SERCA1(-/-) mice was consistent with predicted Mendelian inheritance [1].
• Interestingly, SERCA1 transgenic hearts exhibited super contractility with a significant increase in rates of muscle contraction (+dp/dt) and relaxation (-dp/dT) [10].

Anatomical context of Atp2a1

• PLB via modulation of SERCA can play a major role in regulation of both phasic and tonic smooth muscle contractility [11].
• Phospholamban (PLB) is a 24- to 27-kDa phosphoprotein that modulates activity of the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) [12].
• These findings indicate that ectopic expression of phospholamban in fast-twitch skeletal muscle is associated with inhibition of SERCA1 activity and decreased relaxation rates of this muscle [13].
• To determine the effect of phospholamban expression on SERCA1 activity, microsomes were isolated from transfected and nontransfected C2C12 cell myotubes, and the initial rates of 45Ca(2+)-uptake were determined over a wide range of Ca2+ concentrations (0.1-10 microM) [14].
• Differentiation of C2C12 myoblasts to myotubes was associated with induction of SERCA1 expression, assessed by Western blotting analysis using Ca(2+)-ATPase isoform specific antibodies [14].

Associations of Atp2a1 with chemical compounds

• Phospholamban is a phosphoprotein in the cardiac sarcoplasmic reticulum (SR) which regulates the apparent Ca(2+) affinity of the SR Ca(2+)-ATPase (SERCA2) [15].
• Treatment of wild-type beta-cells with thapsigargin, an inhibitor of SERCA, resulted in an increase in glucose-stimulated fractional insulin secretion similar to that observed in IRS-1-overexpressing cells [16].
• These results show that NF-SLN subcellular distribution depends on SERCA coexpression and on its luminal, C-terminal RSYQY sequence [17].
• SERCA overexpression reduces hydroxyl radical injury in murine myocardium [18].
• Cardiac glycosides such as G-strophanthin (ouabain) bind to and inhibit the plasma membrane Na+,K(+)-ATPase but not the sarcoplasmic reticulum (SR) Ca(2+)-ATPase, whereas thapsigargin specifically blocks the SR Ca(2+)-ATPase [19].

Regulatory relationships of Atp2a1

• In vitro reconstitution and cell culture expression studies have shown that phospholamban can also regulate SERCA1, the fast-twitch skeletal muscle isoform [13].

Other interactions of Atp2a1

• The role of sarcolipin (SLN) in cardiac physiology was critically evaluated by generating a transgenic (TG) mouse model in which the SLN to sarco(endoplasmic)reticulum (SR) Ca(2+) ATPase (SERCA) ratio was increased in the ventricle [20].
• This effect of IRS-1 may be mediated via an interaction with the sarco-endoplasmic reticulum calcium ATPase (SERCA) [16].
• Triadin 1 overexpression was accompanied by time-dependent changes in the protein expression of the ryanodine receptor, junctin, and cardiac/slow-twitch muscle SR Ca(2+)-ATPase isoform [21].
• The SERCA 2a-inhibitor cyclopiazonic acid did not affect myosin ATPase-activity in this system [22].
• We evaluated the importance and role of phospholamban, a protein which inhibits the sarcoplasmic reticulum (SR) calcium ATPase (SERCA), in regulating the contractility of the phasic mouse portal vein [23].

Analytical, diagnostic and therapeutic context of Atp2a1

• RESULTS: Quantitative immunoblotting revealed an increase of 1.8-fold in total SERCA level, while SERCA2 was decreased to 50% of wild types [24].
• Co-immunoprecipitation of IRS-1 and SERCA in CHO-T cells and beta-cells confirms that these proteins do indeed interact directly [16].
• Tissue distribution of the alternatively spliced mRNAs was studied by RT-PCR: SERCA 3b was the only isoform expressed in endothelial cells from aorta and heart and also was the major isoform in lung and kidney whereas SERCA 3a and 3b were coexpressed in trachea, intestine, thymus, spleen, and fetal liver [25].
• Recent studies have shown that decreased expression and activity of SERCA are associated with end-stage heart failure in humans and in experimental animal models of heart failure [4].
• A gene therapy type of approach delivering increased amounts of SERCA or phospholamban mutants leading to increased SERCA activity should therefore be considered in the future [5].

References