The conformation of calsequestrin determines its ability to regulate skeletal ryanodine receptors

Lan Wei, Magdolna Varsányi, Angela F. Dulhunty, Nicole A Beard

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Ca2+ efflux from the sarcoplasmic reticulum decreases when store Ca2+ concentration falls, particularly in skinned fibers and isolated vesicles where luminal Ca2+ can be reduced to very low levels. However ryanodine receptor activity in many single channel studies is higher when the luminal free Ca2+ concentration is reduced. We investigated the hypothesis that prolonged exposure to low luminal Ca2+ causes conformational changes in calsequestrin and deregulation of ryanodine receptors, allowing channel activity to increase. Lowering of luminal Ca2+ from 1 mM to 100 microM for several minutes resulted in conformational changes with dissociation of 65-75% of calsequestrin from the junctional face membrane. The calsequestrin remaining associated no longer regulated channels. In the absence of this regulation, ryanodine receptors were more active when luminal Ca2+ was lowered from 1 mM to 100 microM. In contrast, when ryanodine receptors were calsequestrin regulated, lowering luminal Ca2+ either did not alter or decreased activity. Ryanodine receptors are regulated by calsequestrin under physiological conditions where calsequestrin is polymerized. Since depolymerization occurs slowly, calsequestrin can regulate the ryanodine receptor and prevent excess Ca2+ release when the store is transiently depleted, for example, during high frequency activity or early stages of muscle fatigue.

Original languageEnglish
Pages (from-to)1288-1301
Number of pages14
JournalBiophysical Journal
Volume91
Issue number4
DOIs
Publication statusPublished - 15 Aug 2006
Externally publishedYes

Fingerprint Dive into the research topics of 'The conformation of calsequestrin determines its ability to regulate skeletal ryanodine receptors'. Together they form a unique fingerprint.

  • Cite this