S-nitrosylated Cysteins In The Y522S Ca2+ Release Channel RyR1

Abstract

The Y522S mutation, linked to malignant hyperthermia (MH) and central core diseases in humans, causes a leaky Ca2+ release channel (RyR1), when engineered to mice (RyR1Y522S/wt). The elevated levels of resting Ca2+ in mice harboring the Y522S mutation drive an increased generation of reactive nitrogen species (RNS). S-nitrosylation of the mutant RyR1 increases its temperature sensitivity, resulting in uncontrolled muscle contractions during heat stress, and decreases its sensitivity to Ca2+ inhibition further promoting SR Ca2+ leak, leading to a feedforward cyclic mechanism that continuously increases the temperature sensitivity of RyR1 and RNS production [1].We have used selective isotope coded affinity tag labeling and mass spectroscopy, to identify the cysteines that are endogenously S-nitrosylated in the mutant Ca2+ release channel RyR1 and responsible for its temperature sensitivity.This work was supported by grants from NIH (AR050503 and AR053349) and MDA to SLH[1]. RyR1 S-Nitrosylation Underlies Environmental Heat Stroke and Sudden Death in Y522S RyR1 Knock in Mice, W.J. Durham, P. Aracena-Parks, C. Long, A.E. Rossi, S. A. Goonasekera, S. Boncompagni, D. L. Galvan, C.P. Gilman, M.R. Baker, N. Shirokova, F. Protasi, R. Dirksen, and S.L. Hamilton. Cell, (2008), 133, 53–65.