Dampened activity of ryanodine receptor channels in mutant skeletal muscle lacking TRIC-A.

TRIC-A is a major component of the nuclear and sarcoplasmic reticulum (SR) membranes of cardiac and skeletal muscle, and is localised closely with RyR channels in the SR terminal cisternae. The skeletal muscle of Tric-a KO mice is characterised by Ca2+ overloaded and swollen SR and by changes in the properties of SR Ca2+ release. We therefore investigated if RyR1 gating behaviour is modified in the SR from Tric-a KO mice by incorporating native RyR1 into planar phospholipid bilayers under voltage-clamp conditions. We find that RyR1 channels from Tric-a KO mice respond normally to cytosolic Ca2+, ATP, adenine, caffeine and to luminal Ca2+. However, the channels are more sensitive to the inactivating effects of divalent cations, thus, in the presence of Mg2+, ATP is inadequate as an activator. Additionally, channels are not characteristically activated by PKA even though phosphorylation levels of Ser2844 is similar to controls. Our results suggest that TRIC-A functions as an excitatory modulator of RyR1 channels within SR terminal cisternae. Importantly, this regulatory action of TRIC-A appears to be independent of, although it would be additive to, any indirect consequences to RyR1 activity that would arise due to K+ fluxes across the SR via TRIC-A. This article is protected by copyright. All rights reserved