Disruption of a single copy of the SERCA2 gene results in altered Ca2+ homeostasis and cardiomyocyte function

A mouse model carrying a null mutation in one copy of the sarcoplasmic reti culum (SR) Ca2+-ATPase isoform 2 (SERCA2) gene, in which SERCA2 protein lev els are reduced by similar to 35%, was used to investigate the effects of d ecreased SERCA2 level on intracellular Ca2+ homeostasis and contractile pro perties in isolated cardiomyocytes, When compared with wild-type controls, SR Ca2+ stores and Ca2+ release in myocytes of SERCA2 heterozygous mice wer e decreased by similar to 40-60% and similar to 30-40%, respectively, and t he rate of myocyte shortening and relengthening were each decreased by simi lar to 40%. However, the rate of Ca2+ transient decline (tau) was not alter ed significantly, suggesting that compensation was occurring in the removal of Ca2+ from the cytosol, Phospholamban, which inhibits SERCA2, was decrea sed by similar to 40% in heterozygous hearts, and basal phosphorylation of Ser-16 and Thr-17, which relieves the inhibition, was increased similar to2 - and 2.1-fold. These results indicate that reduced expression and increase d phosphorylation of phospholamban provides compensation for decreased SERC A2 protein levels in heterozygous heart. Furthermore, both expression and c urrent density of the sarcolemmal Na+-Ca2+ exchanger were up-regulated, The se results demonstrate that a decrease in SERCA2 levels can directly modify intracellular Ca2+ homeostasis and myocyte contractility. However, the res ulting deficit is partially compensated by alterations in phospholamban/SER CA2 interactions and by up-regulation of the Na+-Ca2+ exchanger.