title: Alteration of sarcoplasmic reticulum Ca2+ release termination by ryanodine receptor sensitization and in heart failure.
abstract: Many physiological processes and pharmacological agents modulate the ryanodine receptor (RyR), the primary sarcoplasmic reticulum (SR) Ca(2+) release channel in the heart. However, how such modulations translate into functional effects during cardiac excitation-contraction coupling (ECC) is much less clear. Using a low dose (250 microM) of caffeine we sensitized the RyR and examined SR Ca(2+) release using dynamic measurements of cytosolic Ca(2+) ([Ca(2+)](i)) and free Ca(2+) within the SR ([Ca(2+)](SR)). In field stimulated (1 Hz) rabbit ventricular myocytes, application of 250 microM caffeine caused an initial 33% increase in SR Ca(2+) release, which was followed by a decrease in SR Ca(2+) load (28%) and steady-state SR Ca(2+) release (23%). To investigate the effects of caffeine on local SR Ca(2+) release, we measured [Ca(2+)](SR) from individual release junctions during ECC as well as during spontaneous Ca(2+) sparks. In intact myocytes during ECC, caffeine increased global fractional SR Ca(2+) release by decreasing the [Ca(2+)](SR) level at which local release terminated by 21%. Similarly, in permeabilized myocytes during spontaneous Ca(2+) sparks, caffeine decreased the [Ca(2+)](SR) level for release termination by 12%. Finally, we examined if Ca(2+) release termination was changed in myocytes from failing hearts, where remodelling processes lead to altered RyR function. In myocytes from failing rabbit hearts, the [Ca(2+)](SR) termination level for Ca(2+) sparks was 13% lower than that of non-failing myocytes. Collectively, these data suggest that altering the termination level for local Ca(2+) release may represent a novel mechanism to increase SR Ca(2+) release and contractility during ECC.
authors.affiliation: Department of Molecular Biophysics and Physiology, Rush University School of Medicine, 1750 W. Harrison Street, Chicago, IL 60612, USA.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Domeier
authors.forename: Lothar A
authors.initials: LA
authors.lastname: Blatter
authors.forename: Aleksey V
authors.initials: AV
authors.lastname: Zima
mesh_terms: D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002154:Calpain / Q000378:metabolism; D002155:Calsequestrin / Q000172:deficiency; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D006333:Heart Failure / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*
chemical_list: D002155:Calsequestrin; D000697:Central Nervous System Stimulants; D019837:Ryanodine Receptor Calcium Release Channel; D002110:Caffeine; D002154:Calpain; D002118:Calcium