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

Samantha C. Salvage, Esther M. Gallant, Nicole A. Beard, Shiraz Ahmad, Haseeb Valli, James A. Fraser, Christopher L.H. Huang, Angela F. Dulhunty

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)
110 Downloads (Pure)


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.

Original languageEnglish
Article number229039
Pages (from-to)1-14
Number of pages14
JournalJournal of Cell Science
Issue number10
Publication statusPublished - 2019


Dive into the research topics of 'Ion channel gating in cardiac ryanodine receptors from the arrhythmic RyR2-P2328S mouse'. Together they form a unique fingerprint.

Cite this