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- W2079423588 abstract "Rhythmic contraction of cardiac myocytes is maintained by precisely controlled Ca2+ efflux from intracellular stores mediated by the cardiac ryanodine receptor (RyR2). Mutations in RyR2 can cause channel instability leading to perturbed Ca2+ release that can trigger arrhythmias. RyR2-dependent ventricular tachyarrhythmia is an important cause of sudden cardiac death, the mechanistic basis of which remains unclear. Most investigations of RyR2 single channel function have focussed on the secondary effects of mutations on channel function through modulation by regulatory proteins and cellular processes without emphasis on mutation-dependent effects on the gating behaviour of the channel itself. Here we describe the gating kinetics of wild-type hRyR2 when activated by its physiological trigger, cytosolic Ca2+ and isolated from the possible modulatory effects of regulatory factors external to the channel. Single channel experiments were performed using recombinant, purified hRyR2 under reducing conditions where the luminal Ca2+ was buffered at 50 nM while the cytosolic Ca2+ was stringently controlled using EGTA, HEDTA and NTA to achieve an activating free Ca2+ range of 0-500 µM. The sigmoidal dose-response curve yields an EC50 of 1.45±0.44 µM (n=10) and Po saturates at ∼10 µM Ca2+. The gating model describes the kinetic behaviour using a minimum of three open and closed states and incorporates constitutive (unliganded) gating while also revealing very brief closings suggestive of events similar to C-type inactivation in K+ channels. Novel detailed burst analysis of RyR2 elucidates its ligand-bound gating kinetics. The model was further validated by simulation of single channel data. This model provides a firm platform for further analysis of the effects of physiological regulatory factors and dissecting the mechanistic nature of the perturbations in mutant channels causing cardiovascular pathology. Supported by the British Heart Foundation." @default.
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- W2079423588 date "2011-02-01" @default.
- W2079423588 modified "2023-10-17" @default.
- W2079423588 title "A Model-Based Description and Burst Analysis of Purified Human Cardiac Ryanodine Receptor (hRyR2) Gating Kinetics Under Minimal Conditions" @default.
- W2079423588 doi "https://doi.org/10.1016/j.bpj.2010.12.2456" @default.
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