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- W2023781185 abstract "Rationale: The coupled-clock theory of cardiac pacemaker normal automaticity integrates numerous facets of pacemaker cell Ca2+ cycling and electrophysiology. Details of intrinsic RyR molecular mechanisms that regulate spontaneous RyR activation to generate local Ca2+ releases (LCRs) of the “Ca2+ clock”, that drive normal automaticity, however, have not been elucidated. Objective: We hypothesized that spontaneous RyR activation to generate LCRs of the “Ca2+ clock” will be attenuated in cells harboring mutant SR luminal Ca2+ sensor (E4872Q). Methods and Results: We measured the spontaneous beating rate, action potential (AP) triggered RyR Ca2+ releases, characteristics of spontaneous LCRs in single ES derived cardiocytes from wild type (WT) and the RyR mutant (E4872Q) mouse embryonic stem cells (ES) with intact sarcolemma and in permeabilized cells in the absence of AP's, and the expression of SR Ca2+ proteins in SAN lysates. We also measured the heart rate in vivo, which was 15% lower in mutant mice vs WT mice. Compared to WT cardiocytes, cells harboring the RyR mutation had a reduced spontaneous AP firing rate and reduced spontaneous RyR Ca2+ release. Expression of RyR protein was reduced, and calsequestrin and calreticulin were increased in mutant vs that of WT cells. Conclusions: Numerous luminal SR Ca2+ sensing mechanisms linked to regulation of spontaneous RyR activation, regulator of the spontaneous AP firing rate of pacemaker cells. Alterations in spontaneous RyR activation in RyR mutant cells were a mechanism for a reduction of their AP firing rate and for reduced heart rate in mutant mice in vivo." @default.
- W2023781185 created "2016-06-24" @default.
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- W2023781185 date "2015-01-01" @default.
- W2023781185 modified "2023-09-30" @default.
- W2023781185 title "Reduced Heart Rate in Mice Harboring an SR Luminal Ca2+ Sensor Mutation (E4872Q) is Linked to Abnormal Ca2+ Release and Pacemaker Function in Isolated Cardiocytes Derived from the Mutant RyR Clone" @default.
- W2023781185 doi "https://doi.org/10.1016/j.bpj.2014.11.607" @default.
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