title: Changes of SERCA activity have only modest effects on sarcoplasmic reticulum Ca2+ content in rat ventricular myocytes.
abstract: Changes of the activity of the sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) affect the amplitude of the systolic Ca(2+) transient and thence cardiac contractility. This is thought to be due to alterations of SR Ca(2+) content. Recent work on mice in which the expression of SERCA is decreased found that a large reduction of SERCA expression resulted in a proportionately much smaller decrease of SR Ca(2+) content. The aim of the current work was to investigate the quantitative nature of the dependence of both the amplitude of the systolic Ca(2+) transient and SR Ca(2+) content on SERCA activity during acute partial inhibition of SERCA. Experiments were performed on rat ventricular myocytes. Brief application of thapsigargin (1 μm) resulted in a decrease of SERCA activity as measured from the rate of decay of the systolic Ca(2+) transient. This was accompanied by a decrease in the amplitude of the systolic Ca(2+) transient which was linearly related to that of SERCA activity. However, the fractional decrease in the SR Ca(2+) content was much less than that of SERCA activity. On average SR Ca(2+) content was proportional to SERCA activity raised to the 0.38 ± 0.07 power. This shallow dependence of SR content on SERCA activity arises because Ca(2+) release is a steep function of SR Ca(2+) content. In contrast SR Ca(2+) content was increased 4.59 ± 0.40 (n = 8)-fold by decreasing ryanodine receptor opening with tetracaine (1 mm). Therefore a modest decrease of SR Ca(2+) content results in a proportionately larger fall of Ca(2+) release from the SR which can balance a larger initiating decrease of SERCA. In conclusion, the shallow dependence of SR Ca(2+) content on SERCA activity is expected for a system in which small changes of SR Ca(2+) content produce larger effects on the amplitude of the systolic Ca(2+) transient.
authors.affiliation: Unit of Cardiac Physiology, University of Manchester, 46 Grafton Street, Manchester, UK. eisner@man.ac.uk
authors.forename: E F
authors.initials: EF
authors.lastname: Bode
authors.forename: S J
authors.initials: SJ
authors.lastname: Briston
authors.forename: C L
authors.initials: CL
authors.lastname: Overend
authors.forename: S C
authors.initials: SC
authors.lastname: O'Neill
authors.forename: A W
authors.initials: AW
authors.lastname: Trafford
authors.forename: D A
authors.initials: DA
authors.lastname: Eisner
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013599:Systole / Q000187:drug effects; D013748:Tetracaine / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D013748:Tetracaine; D019284:Thapsigargin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium