title: Modeling Ca2+ dynamics of mouse cardiac cells points to a critical role of SERCA's affinity for Ca2+.
abstract: The SERCA2a isoform of the sarco/endoplasmic reticulum Ca(2+) 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 Ca(2+) affinity, but twofold lower maximal turnover rate) can explain these compensatory changes, we simulated Ca(2+) dynamics in mouse ventricular myocytes. The model shows that the relative Ca(2+) transport capacity of SERCA2a and SERCA2b depends on the SERCA concentration. The simulations point to a dominant effect of SERCA2b's higher Ca(2+) affinity over its lower maximal turnover rate. The results suggest that increased systolic and decreased diastolic Ca(2+) levels in unstimulated conditions could contribute to the downregulation of SERCA in SERCA2(b/b) mice. In stress conditions, Ca(2+) 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 β-adrenergic stress.
authors.affiliation: Laboratory of Cellular Transport Systems, Department of Molecular Cell Biology, Katholieke Universiteit Leuven, Campus Gasthuisberg, Leuven, Belgium. Luc.Raeymaekers@med.kuleuven.be
authors.forename: Luc
authors.initials: L
authors.lastname: Raeymaekers
authors.forename: Ilse
authors.initials: I
authors.lastname: Vandecaetsbeek
authors.forename: Frank
authors.initials: F
authors.lastname: Wuytack
authors.forename: Peter
authors.initials: P
authors.lastname: Vangheluwe
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D002451:Cell Compartmentation; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D011485:Protein Binding; D012518:Sarcomeres / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium