Ca2+ uptake by the sarcoplasmic reticulum in ventricular myocytes of the SERCA2b/b mouse is impaired at higher Ca2+ loads only

SERCA2a is the cardiac-specific isoform of Ca(2+)-ATPase of the sarcoplasmic reticulum (SR). A reduction of SERCA2a has been implicated in the contractile dysfunction of heart failure, and partial knockout of the SERCA2 gene (Atp2a2(+/-) mice) reiterated many of the features of heart failure. Yet, mice with a mutation of Atp2a2, resulting in full suppression of the SERCA2a isoform and expression of the SERCA2b isoform only (SERCA2(b/b)), showed only moderate functional impairment, despite a reduction by 40% of the SERCA2 protein levels. We examined in more detail the Ca(2+) handling in isolated cardiac myocytes from SERCA2(b/b). At 0.25 Hz stimulation, the amplitude of the [Ca(2+)](i) transients, SR Ca(2+) content, diastolic [Ca(2+)](i), and density of I(CaL) were comparable between WT and SERCA2(b/b). However, the decline of [Ca(2+)](i) was slower (t(1/2) 154+/-7 versus 131+/-5 ms; P<0.05). Reducing the amplitude of the [Ca(2+)](i) transient (eg, SR depletion), removed the differences in [Ca(2+)](i) decline. In contrast, increasing the Ca(2+) load revealed pronounced reduction of SR Ca(2+) uptake at high [Ca(2+)](i). There was no increase in Na(+)-Ca(2+) exchange protein or function. Theoretical modeling indicated that in the SERCA2(b/b) mouse, the higher Ca(2+) affinity of SERCA2b partially compensates for the 40% reduction of SERCA expression. The lack of SR depletion in the SERCA2(b/b) may also be related to the absence of upregulation of Na(+)-Ca(2+) exchange. We conclude that for SERCA isoforms with increased affinity for Ca(2+), a reduced expression level is better tolerated as Ca(2+) uptake and storage are impaired only at higher Ca(2+).