title: Differential Ca2+ and Sr2+ regulation of intracellular divalent cations release in ventricular myocytes.
abstract: The regulation of the Ca2+ -induced Ca2+ release (CICR) from intracellular stores is a critical step in the cardiac cycle. The inherent positive feedback of CICR should make it a self-regenerating process. It is accepted that CICR must be governed by some negative control, but its nature is still debated. We explore here the importance of the Ca2+ released from sarcoplasmic reticulum (SR) on the mechanisms that may control CICR. Specifically, we compared the effect of replacing Ca2+ with Sr2+ on intracellular Ca2+ signaling in intact cardiac myocytes as well as on the function of single ryanodine receptor (RyR) Ca2+ release channels in panar bilayers. In cells, both CICR and Sr2+ -induced Sr2+ release (SISR) were observed. Action potential induced Ca2+ -transients and spontaneous Ca2+ waves were considerably faster than their Sr2+ -mediated counterparts. However, the kinetics of Ca2+ and Sr2+ sparks was similar. At the single RyR channel level, the affinities of Ca2+ and Sr2+ activation were different but the affinities of Ca2+ and Sr2+ inactivation were similar. Fast Ca2+ and Sr2+ stimuli activated RyR channels equally fast but adaptation (a spontaneous slow transition back to steady-state activity levels) was not observed in the Sr2+ case. Together, these results suggest that regulation of the RyR channel by cytosolic Ca2+ is not involved in turning off the Ca2+ spark. In contrast, cytosolic Ca2+ is important in the propagation global Ca2+ release events and in this regard single RyR channel sensitivity to cytosolic Ca2+ activation, not low-affinity cytosolic Ca2+ inactivation, is a key factor. This suggests that the kinetics of local and global RyR-mediated Ca2+ release signals are affected in a distinct way by different divalent cations in cardiac muscle cells.
authors.affiliation: Centro de Biofisica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela.
authors.forename: M E
authors.initials: ME
authors.lastname: Zoghbi
authors.forename: J A
authors.initials: JA
authors.lastname: Copello
authors.forename: C A
authors.initials: CA
authors.lastname: Villalba-Galea
authors.forename: P
authors.initials: P
authors.lastname: Vélez
authors.forename: P L
authors.initials: PL
authors.lastname: Diaz Sylvester
authors.forename: P
authors.initials: P
authors.lastname: Bolaños
authors.forename: A
authors.initials: A
authors.lastname: Marcano
authors.forename: M
authors.initials: M
authors.lastname: Fill
authors.forename: A L
authors.initials: AL
authors.lastname: Escobar
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002413:Cations, Divalent / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013324:Strontium / Q000378:metabolism*; D013997:Time Factors
chemical_list: D002413:Cations, Divalent; D002118:Calcium; D013324:Strontium