Reactive disulfides trigger Ca2+ release from sarcoplasmic reticulum via an oxidation reaction

N. F. Zaidi, C. F. Lagenaur, J. J. Abramson, Isaac N Pessah, G. Salama

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138 Scopus citations

Abstract

Reactive disulfide compounds (RDSs) with a pyridyl ring adjacent to the S-S bond such as 2,2'-dithiodipyridine (2,2'-DTDP), 4,4'-dithiodipyridine, and N-succinimidyl 3(2-pyridyldithio)propionate (SPDP) trigger Ca2+ release from sarcoplasmic reticulum (SR) vesicles. They are known to specifically oxidize free SH sites via a thiol-disulfide exchange reaction with the stoichiometric production of thiopyridone. Thus, the formation of a mixed S-S bond between an accessible SH site on an SR protein and a RDS causes large increases in SR Ca2+ permeability. Reducing agents, glutathione (GSH) of dithiothreitol reverse the effect of RDSs and permit rapid re-uptake of Ca2+ by the Ca2+, Mg2+-ATPase. The RDSs, 2,2'-DTDP, 4,4'-dithiodipyridine and SPDP displaced [3H]ryanodine binding to the Ca2+-receptor complex at IC50 values of 7.5 ± 0.2, 1.5 ± 0.1, and 15.4 ± 0.1 μM, respectively. RDSs did not alter the rapid initial phase of Ca2+ uptake by the pump, stimulated ATPase activity, and induced release from passively loaded vesicles with nonactivated pumps; thus they act at a Ca2+ release channel and not at the Ca2+, Mg2+-ATPase. Efflux rates increased in 0.25-1.0 mm [Mg2+](free) then decreased in 2-5 mM[Mg2+](free). Adenine nucleotides the oxidation of SHs on SR protein by RDSs and thus reduced Ca2+ efflux rates. However, once RDSs oxidized these SH sites and opened the Ca2+ release pathway, subsequent additions of nucleotides stimulated Ca2+ efflux. In skinned fibers, 2,2'-dithiodipyridine elicited rapid twitches which were blocked by ruthenium red. These results indicate that RDSs trigger Ca2+ release from SR by oxidizing a critical SH group, and thus provide a method to covalently label the protein(s) involved in causing these changes in Ca2+ permeability.

Original languageEnglish (US)
Pages (from-to)21725-21736
Number of pages12
JournalJournal of Biological Chemistry
Volume264
Issue number36
StatePublished - 1989
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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    Zaidi, N. F., Lagenaur, C. F., Abramson, J. J., Pessah, I. N., & Salama, G. (1989). Reactive disulfides trigger Ca2+ release from sarcoplasmic reticulum via an oxidation reaction. Journal of Biological Chemistry, 264(36), 21725-21736.