Regulation of Ryanodine receptors by Calsequestrin: Effect of high luminal Ca2+ and phosphorylation

Nicole A Beard, Marco G Casarotto, Lan Wei, Magdolna Varsányi, Derek R Laver, Angela F. Dulhunty

    Research output: Contribution to journalArticle

    87 Citations (Scopus)

    Abstract

    Calsequestrin, the major calcium sequestering protein in the sarcoplasmic reticulum of muscle, forms a quaternary complex with the ryanodine receptor calcium release channel and the intrinsic membrane proteins triadin and junctin. We have investigated the possibility that calsequestrin is a luminal calcium concentration sensor for the ryanodine receptor. We measured the luminal calcium concentration at which calsequestrin dissociates from the ryanodine receptor and the effect of calsequestrin on the response of the ryanodine receptor to changes in luminal calcium. We provide electrophysiological and biochemical evidence that: 1), luminal calcium concentration of >/=4 mM dissociates calsequestrin from junctional face membrane, whereas in the range of 1-3 mM calsequestrin remains attached; 2), the association with calsequestrin inhibits ryanodine receptor activity, but amplifies its response to changes in luminal calcium concentration; and 3), under physiological calcium conditions (1 mM), phosphorylation of calsequestrin does not alter its ability to inhibit native ryanodine receptor activity when the anchoring proteins triadin and junctin are present. These data suggest that the quaternary complex is intact in vivo, and provides further evidence that calsequestrin is involved in the sarcoplasmic reticulum calcium signaling pathway and has a role as a luminal calcium sensor for the ryanodine receptor.

    Original languageEnglish
    Pages (from-to)3444-3454
    Number of pages11
    JournalBiophysical Journal
    Volume88
    Issue number5
    DOIs
    Publication statusPublished - May 2005

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