Modeling Ca2+ Dynamics of Mouse Cardiac Cells Points to a Critical Role of SERCA's Affinity for Ca2+

The SERCA2a isoform of the sarco/endoplasmic reticulum Ca2+ pumps is specifically expressed in the heart, whereas SERCA2b is the ubiquitously expressed variant. It has been shown previously that replacement of SERCA2a by SERCA2b in mice (SERCA2(b/b) mice) results in only a moderate functional impairment, whereas SERCA activity is decreased by a 40% lower SERCA protein expression and by increased inhibition by phospholamban. To find out whether the documented kinetic differences in SERCA2b relative to SERCA2a (i.e., a twofold higher apparent Ca2+ affinity, but twofold lower maximal turnover rate) can explain these compensatory changes, we simulated Ca2+ dynamics in mouse ventricular myocytes. The model shows that the relative Ca2+ transport capacity of SERCA2a and SERCA2b depends on the SERCA concentration. The simulations point to a dominant effect of SERCA2b's higher Ca2+ affinity over its lower maximal turnover rate. The results suggest that increased systolic and decreased diastolic Ca2+ levels in unstimulated conditions could contribute to the downregulation of SERCA in SERCA2(b/b) mice. In stress conditions, Ca2+ handling is less efficient by SERCA2b than by SERCA2a, which might contribute to the observed hypertrophy in SERCA2(b/b) mice. Altogether, SERCA2a might be a better compromise between performance in basal conditions and performance during beta-adrenergic stress.