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

40 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

Calsequestrin
Ryanodine Receptor Calcium Release Channel
Muscle Fatigue
Sarcoplasmic Reticulum
Membranes

Cite this

Wei, Lan ; Varsányi, Magdolna ; Dulhunty, Angela F. ; Beard, Nicole A. / The conformation of calsequestrin determines its ability to regulate skeletal ryanodine receptors. In: Biophysical Journal. 2006 ; Vol. 91, No. 4. pp. 1288-1301.
@article{6d2bca5725f8432d938ec671aa95ae96,
title = "The conformation of calsequestrin determines its ability to regulate skeletal ryanodine receptors",
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.",
keywords = "Animals, Binding Sites, Calcium, Calsequestrin, Cells, Cultured, Dose-Response Relationship, Drug, Ion Channel Gating, Male, Muscle, Skeletal, Protein Binding, Protein Conformation, Rabbits, Ryanodine Receptor Calcium Release Channel, Sarcoplasmic Reticulum, Signal Transduction, Structure-Activity Relationship",
author = "Lan Wei and Magdolna Vars{\'a}nyi and Dulhunty, {Angela F.} and Beard, {Nicole A}",
year = "2006",
month = "8",
day = "15",
doi = "10.1529/biophysj.106.082610",
language = "English",
volume = "91",
pages = "1288--1301",
journal = "Biophysical Journal",
issn = "0006-3495",
publisher = "Biophysical Society",
number = "4",

}

The conformation of calsequestrin determines its ability to regulate skeletal ryanodine receptors. / Wei, Lan; Varsányi, Magdolna; Dulhunty, Angela F.; Beard, Nicole A.

In: Biophysical Journal, Vol. 91, No. 4, 15.08.2006, p. 1288-1301.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The conformation of calsequestrin determines its ability to regulate skeletal ryanodine receptors

AU - Wei, Lan

AU - Varsányi, Magdolna

AU - Dulhunty, Angela F.

AU - Beard, Nicole A

PY - 2006/8/15

Y1 - 2006/8/15

N2 - 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.

AB - 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.

KW - Animals

KW - Binding Sites

KW - Calcium

KW - Calsequestrin

KW - Cells, Cultured

KW - Dose-Response Relationship, Drug

KW - Ion Channel Gating

KW - Male

KW - Muscle, Skeletal

KW - Protein Binding

KW - Protein Conformation

KW - Rabbits

KW - Ryanodine Receptor Calcium Release Channel

KW - Sarcoplasmic Reticulum

KW - Signal Transduction

KW - Structure-Activity Relationship

U2 - 10.1529/biophysj.106.082610

DO - 10.1529/biophysj.106.082610

M3 - Article

VL - 91

SP - 1288

EP - 1301

JO - Biophysical Journal

JF - Biophysical Journal

SN - 0006-3495

IS - 4

ER -