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Ion channel gating in cardiac ryanodine receptors from the arrhythmic RyR2-P2328S mouse.

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Salvage, Samantha C  ORCID logo
Gallant, Esther M 
Ahmad, Shiraz 
Valli, Haseeb 


Mutations in the cardiac ryanodine receptor Ca2+ release channel (RyR2) can cause deadly ventricular arrhythmias and atrial fibrillation (AF). The RyR2-P2328S mutation produces catecholaminergic polymorphic ventricular tachycardia (CPVT) and AF in hearts from homozygous RyR2P2328S/P2328S (denoted RyR2S/S) mice. We have now examined P2328S RyR2 channels from RyR2S/S hearts. The activity of wild-type (WT) and P2328S RyR2 channels was similar at a cytoplasmic [Ca2+] of 1 mM, but P2328S RyR2 was significantly more active than WT at a cytoplasmic [Ca2+] of 1 µM. This was associated with a >10-fold shift in the half maximal activation concentration (AC50) for Ca2+ activation, from ∼3.5 µM Ca2+ in WT RyR2 to ∼320 nM in P2328S channels and an unexpected >1000-fold shift in the half maximal inhibitory concentration (IC50) for inactivation from ∼50 mM in WT channels to ≤7 μM in P2328S channels, which is into systolic [Ca2+] levels. Unexpectedly, the shift in Ca2+ activation was not associated with changes in sub-conductance activity, S2806 or S2814 phosphorylation or the level of FKBP12 (also known as FKBP1A) bound to the channels. The changes in channel activity seen with the P2328S mutation correlate with altered Ca2+ homeostasis in myocytes from RyR2S/S mice and the CPVT and AF phenotypes.This article has an associated First Person interview with the first author of the paper.



Atrial fibrillation, Catecholaminergic polymorphic ventricular tachycardia, Cytoplasmic Ca2+ activation, Cytoplasmic Ca2+ inactivation, FKBP, P2328S-RyR2 mouse, RyR2 P2328S ion channel, Animals, Arrhythmias, Cardiac, Atrial Fibrillation, Calcium, Cytoplasm, Ion Channel Gating, Mice, Myocytes, Cardiac, Phosphorylation, Ryanodine Receptor Calcium Release Channel

Journal Title

J Cell Sci

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The Company of Biologists


Publisher's own licence
Medical Research Council (MR/M001288/1)
British Heart Foundation (None)
Wellcome Trust (105727/Z/14/Z)
British Heart Foundation (PG/15/12/31280)