Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a
familial arrhythmogenic disorder associated with mutations in the
cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2)
genes. Previous in vitro studies suggested that RyR2 and CASQ2 interact
as parts of a multimolecular Ca$^2+$-signaling complex; however,
direct evidence for such interactions and their potential significance
to myocardial function remain to be determined. We identified a novel
CASQ2 mutation in a young female with a structurally normal heart
and unexplained syncopal episodes. This mutation results in the nonconservative
substitution of glutamine for arginine at amino acid 33 of CASQ2
(R33Q). Adenoviral-mediated expression of CASQ2(R33Q) in adult rat
myocytes led to an increase in excitation-contraction coupling gain
and to more frequent occurrences of spontaneous propagating (Ca$^2+$
waves) and local Ca$^2+$ signals (sparks) with respect to control
cells expressing wild-type CASQ2 (CASQ2WT). As revealed by a Ca$^2+$
indicator entrapped inside the sarcoplasmic reticulum (SR) of permeabilized
myocytes, the increased occurrence of spontaneous Ca$^2+$ sparks
and waves was associated with a dramatic decrease in intra-SR Ca$^2+$.
Recombinant CASQ2WT and CASQ2R33Q exhibited similar Ca$^2+$-binding
capacities in vitro; however, the mutant protein lacked the ability
of its WT counterpart to inhibit RyR2 activity at low luminal Ca$^2+$
in planar lipid bilayers. We conclude that the R33Q mutation disrupts
interactions of CASQ2 with the RyR2 channel complex and impairs regulation
of RyR2 by luminal Ca$^2+$. These results show that intracellular
Ca$^2+$ cycling in normal heart relies on an intricate interplay
of CASQ2 with the proteins of the RyR2 channel complex and that disruption
of these interactions can lead to cardiac arrhythmia.
%0 Journal Article
%1 Tere_2006_1151
%A Terentyev, Dmitry
%A Nori, Alessandra
%A Santoro, Massimo
%A Viatchenko-Karpinski, Serge
%A Kubalova, Zuzana
%A Gyorke, Inna
%A Terentyeva, Radmila
%A Vedamoorthyrao, Srikanth
%A Blom, Nico A
%A Valle, Giorgia
%A Napolitano, Carlo
%A Williams, Simon C
%A Volpe, Pompeo
%A Priori, Silvia G
%A Gyorke, Sandor
%D 2006
%J Circ. Res.
%K Acid Amino Animals; Arginine; Artificial, Binding, Calcium Calcium, Calsequestrin, Cardiac Cardiac, Catecholamines, Channel, Competitive; Death, Exercise; Female; Glutamine; Humans; Intracellular Membranes, Mutation; Myocytes, Pacing, Patch-Clamp Proteins, Rats; Receptor Recombinant Release Reticulum, Ryanodine Sarcoplasmic Substitution; Sudden, Syncope, Tachycardia, Techniques; Ventricular, etiology; genetics/metabolism/physiopathology genetics/metabolism; genetics; metabolism; methods;
%N 9
%P 1151--1158
%R 10.1161/01.RES.0000220647.93982.08
%T Abnormal interactions of calsequestrin with the ryanodine receptor
calcium release channel complex linked to exercise-induced sudden
cardiac death.
%U http://dx.doi.org/10.1161/01.RES.0000220647.93982.08
%V 98
%X Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a
familial arrhythmogenic disorder associated with mutations in the
cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2)
genes. Previous in vitro studies suggested that RyR2 and CASQ2 interact
as parts of a multimolecular Ca$^2+$-signaling complex; however,
direct evidence for such interactions and their potential significance
to myocardial function remain to be determined. We identified a novel
CASQ2 mutation in a young female with a structurally normal heart
and unexplained syncopal episodes. This mutation results in the nonconservative
substitution of glutamine for arginine at amino acid 33 of CASQ2
(R33Q). Adenoviral-mediated expression of CASQ2(R33Q) in adult rat
myocytes led to an increase in excitation-contraction coupling gain
and to more frequent occurrences of spontaneous propagating (Ca$^2+$
waves) and local Ca$^2+$ signals (sparks) with respect to control
cells expressing wild-type CASQ2 (CASQ2WT). As revealed by a Ca$^2+$
indicator entrapped inside the sarcoplasmic reticulum (SR) of permeabilized
myocytes, the increased occurrence of spontaneous Ca$^2+$ sparks
and waves was associated with a dramatic decrease in intra-SR Ca$^2+$.
Recombinant CASQ2WT and CASQ2R33Q exhibited similar Ca$^2+$-binding
capacities in vitro; however, the mutant protein lacked the ability
of its WT counterpart to inhibit RyR2 activity at low luminal Ca$^2+$
in planar lipid bilayers. We conclude that the R33Q mutation disrupts
interactions of CASQ2 with the RyR2 channel complex and impairs regulation
of RyR2 by luminal Ca$^2+$. These results show that intracellular
Ca$^2+$ cycling in normal heart relies on an intricate interplay
of CASQ2 with the proteins of the RyR2 channel complex and that disruption
of these interactions can lead to cardiac arrhythmia.
@article{Tere_2006_1151,
abstract = {Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a
familial arrhythmogenic disorder associated with mutations in the
cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2)
genes. Previous in vitro studies suggested that RyR2 and CASQ2 interact
as parts of a multimolecular {C}a$^{2+}$-signaling complex; however,
direct evidence for such interactions and their potential significance
to myocardial function remain to be determined. We identified a novel
CASQ2 mutation in a young female with a structurally normal heart
and unexplained syncopal episodes. This mutation results in the nonconservative
substitution of glutamine for arginine at amino acid 33 of CASQ2
(R33Q). Adenoviral-mediated expression of CASQ2(R33Q) in adult rat
myocytes led to an increase in excitation-contraction coupling gain
and to more frequent occurrences of spontaneous propagating ({C}a$^{2+}$
waves) and local {C}a$^{2+}$ signals (sparks) with respect to control
cells expressing wild-type CASQ2 (CASQ2WT). As revealed by a {C}a$^{2+}$
indicator entrapped inside the sarcoplasmic reticulum (SR) of permeabilized
myocytes, the increased occurrence of spontaneous {C}a$^{2+}$ sparks
and waves was associated with a dramatic decrease in intra-SR [{C}a$^{2+}$].
Recombinant CASQ2WT and CASQ2R33Q exhibited similar {C}a$^{2+}$-binding
capacities in vitro; however, the mutant protein lacked the ability
of its WT counterpart to inhibit RyR2 activity at low luminal [{C}a$^{2+}$]
in planar lipid bilayers. We conclude that the R33Q mutation disrupts
interactions of CASQ2 with the RyR2 channel complex and impairs regulation
of RyR2 by luminal {C}a$^{2+}$. These results show that intracellular
{C}a$^{2+}$ cycling in normal heart relies on an intricate interplay
of CASQ2 with the proteins of the RyR2 channel complex and that disruption
of these interactions can lead to cardiac arrhythmia.},
added-at = {2009-06-03T11:20:58.000+0200},
author = {Terentyev, Dmitry and Nori, Alessandra and Santoro, Massimo and Viatchenko-Karpinski, Serge and Kubalova, Zuzana and Gyorke, Inna and Terentyeva, Radmila and Vedamoorthyrao, Srikanth and Blom, Nico A and Valle, Giorgia and Napolitano, Carlo and Williams, Simon C and Volpe, Pompeo and Priori, Silvia G and Gyorke, Sandor},
biburl = {https://www.bibsonomy.org/bibtex/2bfc92a47c098100b12ba5623a232a650/hake},
description = {The whole bibliography file I use.},
doi = {10.1161/01.RES.0000220647.93982.08},
file = {Tere_2006_1151.pdf:Tere_2006_1151.pdf:PDF},
institution = {Department of Physiology and Cell Biology, Heart and Lung Research
Institute, Ohio State University, Columbus, OH 43210, USA.},
interhash = {2d99a59662dca9504678882c9b26247d},
intrahash = {bfc92a47c098100b12ba5623a232a650},
journal = {Circ. Res.},
keywords = {Acid Amino Animals; Arginine; Artificial, Binding, Calcium Calcium, Calsequestrin, Cardiac Cardiac, Catecholamines, Channel, Competitive; Death, Exercise; Female; Glutamine; Humans; Intracellular Membranes, Mutation; Myocytes, Pacing, Patch-Clamp Proteins, Rats; Receptor Recombinant Release Reticulum, Ryanodine Sarcoplasmic Substitution; Sudden, Syncope, Tachycardia, Techniques; Ventricular, etiology; genetics/metabolism/physiopathology genetics/metabolism; genetics; metabolism; methods;},
month = May,
number = 9,
pages = {1151--1158},
pdf = {Tere_2006_1151.pdf},
pii = {01.RES.0000220647.93982.08},
pmid = {16601229},
timestamp = {2009-06-03T11:21:34.000+0200},
title = {Abnormal interactions of calsequestrin with the ryanodine receptor
calcium release channel complex linked to exercise-induced sudden
cardiac death.},
url = {http://dx.doi.org/10.1161/01.RES.0000220647.93982.08},
volume = 98,
year = 2006
}