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J Gen Physiol. 2013 Aug;142(2):127-36. doi: 10.1085/jgp.201311022. Epub 2013 Jul 15.

Mechanism of calsequestrin regulation of single cardiac ryanodine receptor in normal and pathological conditions.

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1
Department of Molecular Physiology and Biophysics, Rush University Medical Center, Chicago, IL 60612, USA.

Abstract

Release of Ca(2+) from the sarcoplasmic reticulum (SR) drives contractile function of cardiac myocytes. Luminal Ca(2+) regulation of SR Ca(2+) release is fundamental not only in physiology but also in physiopathology because abnormal luminal Ca(2+) regulation is known to lead to arrhythmias, catecholaminergic polymorphic ventricular tachycardia (CPVT), and/or sudden cardiac arrest, as inferred from animal model studies. Luminal Ca(2+) regulates ryanodine receptor (RyR)2-mediated SR Ca(2+) release through mechanisms localized inside the SR; one of these involves luminal Ca(2+) interacting with calsequestrin (CASQ), triadin, and/or junctin to regulate RyR2 function. CASQ2-RyR2 regulation was examined at the single RyR2 channel level. Single RyR2s were incorporated into planar lipid bilayers by the fusion of native SR vesicles isolated from either wild-type (WT), CASQ2 knockout (KO), or R33Q-CASQ2 knock-in (KI) mice. KO and KI mice have CPVT-like phenotypes. We show that CASQ2(WT) action on RyR2 function (either activation or inhibition) was strongly influenced by the presence of cytosolic MgATP. Function of the reconstituted CASQ2(WT)-RyR2 complex was unaffected by changes in luminal free [Ca(2+)] (from 0.1 to 1 mM). The inhibition exerted by CASQ2(WT) association with the RyR2 determined a reduction in cytosolic Ca(2+) activation sensitivity. RyR2s from KO mice were significantly more sensitive to cytosolic Ca(2+) activation and had significantly longer mean open times than RyR2s from WT mice. Sensitivity of RyR2s from KI mice was in between that of RyR2 channels from KO and WT mice. Enhanced cytosolic RyR2 Ca(2+) sensitivity and longer RyR2 open times likely explain the CPVT-like phenotype of both KO and KI mice.

PMID:
23858002
PMCID:
PMC3727306
DOI:
10.1085/jgp.201311022
[Indexed for MEDLINE]
Free PMC Article
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