Redox regulation of calcium release in skeletal and cardiac muscle

in skeletal and cardiac muscle cells, specific isoforms of the ryanodine receptor channels mediate ca2+ release from the sarcoplasmic reticulum. these channels are highly susceptible to redox modifications, which regulate channel activity. in this work, we studied the effects of ca2+ (endogenous agonist) and mg2+ (endogenous inhibitor) on the kinetics of ca2+ release from sarcoplasmic reticulum vesicles isolated from skeletal or cardiac mammalian muscle. native skeletal vesicles exhibited maximal stimulation of release kinetics by 10-20 μm [ca2+], whereas in native cardiac vesicles, maximal stimulation of release required only 1 μm [ca2+]. in 10 μm [ca2+], free [mg2+] < 0.1 mm produced marked inhibition of release from skeletal vesicles but free [mg2+] - 0.8 mm did not affect release from cardiac vesicles. incubation of skeletal or cardiac vesicles with the oxidant thimerosal increased their susceptibility to stimulation by ca2+ and decreased the inhibitory effect of mg2+ in skeletal vesicles. sulfhydryl-reducing agents fully reversed the effects of thimerosal. the endogenous redox species, glutathione disulfide and s-nitrosoglutathione, also stimulated release from skeletal sarcoplasmic reticulum vesicles. in 10 μm [ca2+], 35s-nitrosoglutathione labeled a protein fraction enriched in release channels through s-glutathiolation. free [mg2+] 1 mm or decreasing free [ca2+] to the nm range prevented this reaction. possible physiological and pathological consequences of redox modification of release channels on ca2+ signaling in heart and muscle cells are discussed