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How Many Cysteine Residues Regulate Ryanodine Receptor Channel Activity

Date

2000

Authors

Dulhunty, Angela
Haarmann, Claudia
Green, Daniel
Hart, James

Journal Title

Journal ISSN

Volume Title

Publisher

Mary Ann Liebert Inc.

Abstract

RyRs contain 80-100 cysteine residues per subunit, of which ~25% are free for covalent modification, while the remainder are either modified or form intraprotein disulfides. Oxidizing and nitrosylating reagents have several effects on single RyR channel activity, which depend on the type of modifying reagent, the isoform of the RyR, and ligands bound to the channel. We present evidence here for four major classes of functional cysteine residues associated with RyR channels, i.e., two classes with free -SH groups that either activate or inhibit channels when covalently modified and two classes, with endogenous modification, that either inhibit or activate. Single-channel characteristics provide evidence for four discrete responses within the first activating class, two responses within the second inhibiting class and two types of response within the third endogenously modified class. All but one of these changes in channel properties depend on residues located on the cytoplasmic or membrane-associated domains of the RyR; the remaining response is confined to the luminal domain. If it is assumed that each type of response depends on a separate subclass of cysteine residue and that each subclass contains a minimum of one cysteine per subunit, our results suggest that there are at least nine cysteine residues per subunit with functional connections to the gating mechanism of RyR channels. These cysteine residues may be selectively modified under physiological and pathological conditions to regulate Ca2+ release from the sarcoplasmic reticulum and contraction.

Description

Keywords

Keywords: calcium channel; cysteine; disulfide; ryanodine receptor; thiol group; thiol reagent; calcium transport; cell membrane; channel gating; chemical modification; covalent bond; cytoplasm; disulfide bond; human; muscle contraction; nonhuman; oxidation reducti

Citation

Source

Antioxidants and Redox Signaling

Type

Journal article

Book Title

Entity type

Access Statement

License Rights

DOI

Restricted until

2037-12-31