Redox regulation of calcium release in skeletal and cardiac muscle

Biol Res. 2002;35(2):183-93. doi: 10.4067/s0716-97602002000200009.


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 microM [Ca2+], whereas in native cardiac vesicles, maximal stimulation of release required only 1 microM [Ca2+]. In 10 microM [Ca2+], free [Mg2+] < 0.1 mM produced marked inhibition of release from skeletal vesicles but free [Mg2+] < or = 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 microM [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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium Signaling / drug effects
  • Dogs
  • Glutathione Disulfide / pharmacology
  • Magnesium / pharmacology
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Myocardium / cytology
  • Myocardium / metabolism*
  • Nitric Oxide Donors / pharmacology
  • Oxidation-Reduction
  • Preservatives, Pharmaceutical / pharmacology
  • Rabbits
  • Ryanodine Receptor Calcium Release Channel / physiology*
  • S-Nitrosoglutathione / pharmacology
  • Sarcoplasmic Reticulum / drug effects
  • Sarcoplasmic Reticulum / metabolism*
  • Thimerosal / pharmacology


  • Nitric Oxide Donors
  • Preservatives, Pharmaceutical
  • Ryanodine Receptor Calcium Release Channel
  • Thimerosal
  • S-Nitrosoglutathione
  • Magnesium
  • Calcium
  • Glutathione Disulfide