%0 Journal Article %1 Kuba_2004_515 %A Kubalova, Zuzana %A Gy�rke, Inna %A Terentyeva, Radmila %A Viatchenko-Karpinski, Serge %A Terentyev, Dmitry %A Williams, Simon C %A Gy�rke, Sandor %D 2004 %J J. Physiol. %K Animals; Caffeine, Calcium Calsequestrin, Cardiac, Cytosol, Male; Myocytes, Rats, Rats; Reticulum, Sarcoplasmic Signaling, Sprague-Dawley; biosynthesis/genetics/physiology; drug effects/genetics/metabolism effects/metabolism; effects/physiology; pharmacology; %N Pt 2 %P 515--524 %R 10.1113/jphysiol.2004.073940 %T Modulation of cytosolic and intra-sarcoplasmic reticulum calcium waves by calsequestrin in rat cardiac myocytes. %U http://dx.doi.org/10.1113/jphysiol.2004.073940 %V 561 %X Waves of Ca$^2+$-induced Ca$^2+$ release occur in various cell types and are involved in the pathology of certain forms of cardiac arrhythmia. These arrhythmias include catecholaminergic polymorphic ventricular tachycardia (CPVT), certain cases of which are associated with mutations in the cardiac calsequestrin gene (CASQ2). To explore the mechanisms of Ca$^2+$ wave generation and unravel the underlying causes of CPVT, we investigated the effects of adenoviral-mediated changes in CASQ2 protein levels on the properties of cytosolic and sarcoplasmic reticulum (SR) Ca$^2+$ waves in permeabilized rat ventricular myocytes. The free Ca$^2+$ inside the sarcoplasmic reticulum (Ca$^2+$SR) was monitored by fluo-5N entrapped into the SR, and cytosolic Ca$^2+$ was imaged using fluo-3. Overexpression of CASQ2 resulted in significant increases in the amplitude of Ca$^2+$ waves and interwave intervals, whereas reduced CASQ2 levels caused drastic reductions in the amplitude and period of Ca$^2+$ waves. CASQ2 abundance had no impact on resting diastolic Ca$^2+$SR or on the amplitude of the Ca$^2+$SR depletion signal during the Ca$^2+$ wave. However, the recovery dynamics of Ca$^2+$SR following Ca$^2+$ release were dramatically altered as the rate of Ca$^2+$SR recovery increased approximately 3-fold in CASQ2-overexpressing myocytes and decreased to 30\% of control in CASQ2-underexpressing myocytes. There was a direct linear relationship between Ca$^2+$ wave period and the half-time of basal Ca$^2+$SR recovery following Ca$^2+$ release. Loading the SR with the low affinity exogenous Ca$^2+$ buffer citrate exerted effects quantitatively similar to those observed on overexpressing CASQ2. We conclude that free intra-SR Ca$^2+$ is a critical determinant of cardiac Ca$^2+$ wave generation. Our data indicate that reduced intra-SR Ca$^2+$ binding activity promotes the generation of Ca$^2+$ waves by accelerating the dynamics of attaining a threshold free Ca$^2+$SR required for Ca$^2+$ wave initiation, potentially accounting for arrhythmogenesis in CPVT linked to mutations in CASQ2.

@article{Kuba_2004_515, abstract = {Waves of {C}a$^{2+}$-induced {C}a$^{2+}$ release occur in various cell types and are involved in the pathology of certain forms of cardiac arrhythmia. These arrhythmias include catecholaminergic polymorphic ventricular tachycardia (CPVT), certain cases of which are associated with mutations in the cardiac calsequestrin gene (CASQ2). To explore the mechanisms of {C}a$^{2+}$ wave generation and unravel the underlying causes of CPVT, we investigated the effects of adenoviral-mediated changes in CASQ2 protein levels on the properties of cytosolic and sarcoplasmic reticulum (SR) {C}a$^{2+}$ waves in permeabilized rat ventricular myocytes. The free [{C}a$^{2+}$] inside the sarcoplasmic reticulum ([{C}a$^{2+}$]SR) was monitored by fluo-5N entrapped into the SR, and cytosolic {C}a$^{2+}$ was imaged using fluo-3. Overexpression of CASQ2 resulted in significant increases in the amplitude of {C}a$^{2+}$ waves and interwave intervals, whereas reduced CASQ2 levels caused drastic reductions in the amplitude and period of {C}a$^{2+}$ waves. CASQ2 abundance had no impact on resting diastolic [{C}a$^{2+}$]SR or on the amplitude of the [{C}a$^{2+}$]SR depletion signal during the {C}a$^{2+}$ wave. However, the recovery dynamics of [{C}a$^{2+}$]SR following {C}a$^{2+}$ release were dramatically altered as the rate of [{C}a$^{2+}$]SR recovery increased approximately 3-fold in CASQ2-overexpressing myocytes and decreased to 30\% of control in CASQ2-underexpressing myocytes. There was a direct linear relationship between {C}a$^{2+}$ wave period and the half-time of basal [{C}a$^{2+}$]SR recovery following {C}a$^{2+}$ release. Loading the SR with the low affinity exogenous {C}a$^{2+}$ buffer citrate exerted effects quantitatively similar to those observed on overexpressing CASQ2. We conclude that free intra-SR [{C}a$^{2+}$] is a critical determinant of cardiac {C}a$^{2+}$ wave generation. Our data indicate that reduced intra-SR {C}a$^{2+}$ binding activity promotes the generation of {C}a$^{2+}$ waves by accelerating the dynamics of attaining a threshold free [{C}a$^{2+}$]SR required for {C}a$^{2+}$ wave initiation, potentially accounting for arrhythmogenesis in CPVT linked to mutations in CASQ2.}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Kubalova, Zuzana and Gy�rke, Inna and Terentyeva, Radmila and Viatchenko-Karpinski, Serge and Terentyev, Dmitry and Williams, Simon C and Gy�rke, Sandor}, biburl = {https://www.bibsonomy.org/bibtex/2292fb010be1612dbf83e0ecc14baa5ef/hake}, description = {The whole bibliography file I use.}, doi = {10.1113/jphysiol.2004.073940}, file = {Kuba_2004_515.pdf:Kuba_2004_515.pdf:PDF}, institution = {Texas Tech University HSC, Lubbock, USA.}, interhash = {fbe6dac97b53e6276c20fbb80a23a95b}, intrahash = {292fb010be1612dbf83e0ecc14baa5ef}, journal = {J. Physiol.}, keywords = {Animals; Caffeine, Calcium Calsequestrin, Cardiac, Cytosol, Male; Myocytes, Rats, Rats; Reticulum, Sarcoplasmic Signaling, Sprague-Dawley; biosynthesis/genetics/physiology; drug effects/genetics/metabolism effects/metabolism; effects/physiology; pharmacology;}, month = Dec, number = {Pt 2}, pages = {515--524}, pdf = {Kuba_2004_515.pdf}, pii = {jphysiol.2004.073940}, pmid = {15486014}, timestamp = {2009-06-03T11:21:18.000+0200}, title = {Modulation of cytosolic and intra-sarcoplasmic reticulum calcium waves by calsequestrin in rat cardiac myocytes.}, url = {http://dx.doi.org/10.1113/jphysiol.2004.073940}, volume = 561, year = 2004 }