Hydrogen Peroxide Stimulates the Ca2+ Release Channel from Skeletal Muscle Sarcoplasmic Reticulum

Multiple Classes of Sulfhydryls Modulate the Skeletal Muscle Ca2+ Release Channel

“…Diamide-induced cross-links are detected in intact membranes, in detergent-solubilized membranes, and in purified ryanodine-binding proteins, 3 suggesting that the cross-links are occurring between subunits of a tetramer. Extended incubations with diamide lead to the formation of higher molecular weight oligomers, which could be trimers or tetramers.…”

“…In diamide cross-linking experiments with either membranes (Fig. 4A) or purified Ca 2ϩ release channel, 3 the 565-kDa band disappeared and a new band was seen with an electrophoretic mobility consistent with dimer formation. Approximate molecular mass values of the oligomers were determined using a 200-kDa myosin standard and the fulllength ryanodine-binding protein as a 565-kDa standard.…”

“…These studies led Abramson and Salama (10) to propose a model for redox modulation of the channel that involves three different sulfhydryl groups that exist in close proximity and that can form mixed disulfides to open or close the channel. The evidence that the channel can be altered by oxidation is conclusive (3)(4)(5)(6)(7)(8)(9)(10)(11); the question is whether this oxidation plays a physiological role in skeletal muscle. It is not yet known if disulfide interchange or oxidation-reduction of sulfhydryls on the Ca 2ϩ release channel contribute to normal excitation-contraction coupling, but an increasing body of evidence suggests that such a mechanism could be an important modulatory element.…”

“…The channel opens in response to a signal from the transverse tubules, which is triggered by membrane depolarization (2), and the resulting flux of Ca 2ϩ from the sarcoplasmic reticulum initiates the sequence of events that leads to muscle contraction. Several laboratories have clearly demonstrated that the activity of the Ca 2ϩ release channel is modulated by oxidation-reduction reactions (3)(4)(5)(6)(7)(8)(9)(10)(11). Oxidizing agents that stimulate Ca 2ϩ release from the sarcoplasmic reticulum include H 2 O 2 (3), 2,2Ј-dithiodipyridine, 4,4Ј-dithiodipyridine (4), Cu 2ϩ phthalocyanine dyes (5), anthraquinone doxorubicin (6,7), and thimerosal (8).…”

Doxorubicin-induced reactive oxygen species generation and intracellular Ca2+increase are reciprocally modulated in rat cardiomyocytes

“…The DOX-mediated Ca 2+ release was blocked by pretreatment with an antioxidants, α-lipoic acid or α-tocopherol, indicating that ROS causes opening of the receptor. Although the causative mechanism of ROS-mediated RyR opening is not clearly understood, the receptor is known to be sensitive to oxidation due to presence of a large number of thiols (Favero et al, 1995). In addition, quinone-containing compounds such as DOX, 1,4-benzoquinone, and 1,4-naphtoquinone are shown to open RyR by oxidizing essential thiols in RyR (Feng et al, 1999).…”