Sulfhydryl oxidation induces rapid calcium release from sarcoplasmic reticulum vesicles.
Micromolar concentrations of cupric ion (Cu2+) and mercaptans such as cysteine, cysteamine, and homocysteine trigger large and rapid Ca2+ release from skeletal muscle sarcoplasmic reticulum (SR) vesicles. At the concentrations used, Cu2+ alone does not induce Ca2+ release nor does cysteine alone; both are required to induce Ca2+ release from SR. Cu2+ is known to catalyze the autooxidation of cysteine to its disulfide form cystine; Cu2+/mercaptan-induced Ca2+ release appears to be caused by Cu2+-catalyzed formation of a mixed disulfide between the exogenous mercaptan and a critical sulfhydryl on a transmembrane protein. In the oxidized state the SR is highly permeable to Ca2+. Supporting evidence for this interpretation is as follows. The order of Ca2+-releasing reactivity of the mercaptans is the same as the order in which these compounds undergo oxidation to disulfide forms in the presence of Cu2+. Ca2+ efflux induced by cysteine and Cu2+ can be reversed by the addition of the disulfide reducing agent dithiothreitol. Hypochlorous acid and plumbagin, both potential sulfhydryl oxidants, induce rapid Ca2+ efflux from SR vesicles; in addition, Cu2+, which catalyzes H2O2 oxidation of cysteine, enhances H2O2-induced release. Oxidation-induced Ca2+ release from SR can be partially reversed or blocked by ruthenium red or the local anesthetics procaine and tetracaine. The Ca2+ efflux rates are strongly Mg2+ dependent and are significantly higher in heavy SR than in light SR. These data suggest that the Ca2+ efflux thus induced is via the "Ca2+ release channel" and that the oxidation state of a critical sulfhydryl group on this protein may be the principal means by which the Ca2+ permeability of the SR is regulated in vivo.
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003300:Copper / Q000494:pharmacology; D003545:Cysteine / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008274:Magnesium / Q000494:pharmacology; D009994:Osmolar Concentration; D010084:Oxidation-Reduction; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000378:metabolism*
D013438:Sulfhydryl Compounds; D003300:Copper; D008274:Magnesium; D003545:Cysteine; D002118:Calcium