Classes of Thiols That Influence the Activity of the Skeletal Muscle Calcium Release Channel

Abstract

The skeletal muscle Ca 2؉ release channel/ryanodine receptor (RyR1) is a prototypic redox-responsive ion channel. Nearly half of the 101 cysteines per RyR1 subunit are kept in a reduced (free thiol) state under conditions comparable with resting muscle. Here we assessed the effects of physiological determinants of cellular redox state (oxygen tension, reduced (GSH) or oxidized (GSSG) glutathione, and NO/O 2 . (released by 3-morpholinosydnonimine)) on RyR1 redox state and activity. Oxidation of ϳ10 RyR1 thiols (from ϳ48 to ϳ38 thiols/RyR1 subunit) had little effect on channel activity. Channel activity increased reversibly as the number of thiols was further reduced to ϳ23/subunit, whereas more extensive oxidation (to ϳ13 thiols/subunit) inactivated the channel irreversibly. Neither S-nitrosylation nor tyrosine nitration contributed to these effects. The results identify at least three functional classes of RyR1 thiols and suggest that 1) the channel may be protected from oxidation by a large reservoir of functionally inert thiols, 2) the channel may be designed to respond to moderate oxidative stress by a change in activation setpoint, and 3) the channel is susceptible to oxidative injury under more extensive conditions.

Regulation of nitric oxide production in limb and ventilatory muscles during chronic exercise training

“…Moreover, endogenous NO production inside muscle fibers serves an important function as an antioxidant by directly scavenging oxygen radicals and by modifying the influence of oxygen radicals on excitation-contraction coupling. Indeed, NO modulates the activity of sarcoplasmic reticulum ryanodine receptors and Ca 2ϩ release through S-nitrosylation of critical cystein residues (25). NO also protects these receptors from the deleterious effects of oxygen radicals that elicit disulfide bond formation of critical cystein residues (24).…”

Feeding wet distillers grains plus solubles contributes to sarcoplasmic reticulum membrane instability

“…The RyR1 of SR membrane possesses several highly reactive sulfhydryl (SH) groups that are susceptible to oxidation (Sun et al 2001). Abramson and Salama (1989) reported that oxidised SH groups can stimulate calcium release by forming disulfide bonds, which cause the RyR1 to maintain in the open state.…”

Le récepteur de la ryanodine de type I

“…Chaque sous-unité compte entre 38 et 48 thiols à l'état libre, sensibles à l'oxydation. L'état d'activation de RYR1 répond de manière biphasique à l'administration de doses croissantes d'oxydants, le maximum d'activation se situant pour un état impliquant 23 SH/RYR1 [2]. L'oxyde nitrique NO est également considéré comme un modulateur physiologique de l'état redox de RYR1 par S-nitrosylation [3].…”

“…Cependant les mécanismes exacts impliqués dans ce processus inflammatoire restent mal connus. Dans deux revues récentes, les équipes de Randal Kaufman et Laurie Glimcher ont décrit le rôle potentiel des voies de signalisation du stress émanant du réticulum endoplasmique (RE) dans l'inflammation et la réponse immunitaire [1,2]. Cette réponse cellulaire intégrée -appelée Unfolded Protein Response (UPR) -est activée en réponse à une accumulation de protéines mal conformées dans la lumière du RE.…”