scholarly journals Dual role of junctin in the regulation of ryanodine receptors and calcium release in cardiac ventricular myocytes

2011 ◽  
Vol 589 (24) ◽  
pp. 6063-6080 ◽  
Author(s):  
Beth A. Altschafl ◽  
Demetrios A. Arvanitis ◽  
Oscar Fuentes ◽  
Qunying Yuan ◽  
Evangelia G. Kranias ◽  
...  
Keyword(s):  
Calcium Release ◽  
Ventricular Myocytes ◽  
Ryanodine Receptors ◽  
Dual Role ◽  
Cardiac Ventricular Myocytes

Abstract 18111: Flecainide Exerts its Antiarrhythmic Action in CPVT Through Blockade of Neuronal Na+ channel-mediated Arrhythmogenic Diastolic Ca2+ Release

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Przemyslaw Radwanski ◽  
Hsiang-Ting Ho ◽  
Björn Knollmann ◽  
Andriy Belevych ◽  
Sándor Györke
Keyword(s):  
Ventricular Myocytes ◽  
Ryanodine Receptors ◽  
Cellular Level ◽  
Antiarrhythmic Effect ◽  
Na Channel ◽  
Antiarrhythmic Action ◽  
Pharmacological Interventions ◽  
Cellular Excitability

Background: Flecaininde is an effective antiarrhythmic in management of CPVT. Its antiarrhythmic action has been attributed to direct effect on RyR2 and reduced cellular excitability through the inhibition of cardiac-type Na + channels. Recently we demonstrated that neuronal Na + channels (nNa v s) colocalize with the ryanodine receptors (RyR2) Ca 2+ release channels on the sarcoplasmic reticulum. Here we explore a novel mechanism that may contribute to the antiarrhythmic effect of flecainide, mainly uncoupling of aberrant Na + /Ca 2+ signaling through nNa v inhibition. Methods: To study the effects of flecainide on Ca 2+ signaling we used a murine model of cardiac calsequestrin-associated CPVT. We performed confocal microscopy in intact isolated ventricular myocytes to assess Ca 2+ handling and recorded late Na + current (I Na ) during various pharmacological interventions. Surface electrocardiograms were performed during catecholamine challenge to monitor arrhythmic activity in vivo . Results: During catecholamine stimulation with isoproterenol (Iso; 100 nM) disruption of the cross-talk between nNa v s and RyR2 by nNa v blockade with 100nM tetrodotoxin (TTX) and riluzole (10μM) as well as flecainide (2.5μM) reduced Iso-promoted late I Na and DCR in isolated intact CPVT cardiomyocytes. To further examine the role of nNa v -mediated late I Na in genesis of DCR we augmented nNa v channel activity with β-Pompilidotoxin (β-PMTX, 40μM). Effects of β-PMTX in CPVT cardiomyocytes were reversed by nNa v blockade with TTX and riluzole as well as flecainide. This reduction in late I Na and DCR frequency with riluzole and flecainide in the presence of β-PMTX on cellular level translated to decreased ventricular arrhythmias in CPVT mice. Conclusion: These data suggest that disruption of nNa v -mediated late I Na can prevent arrhythmogenic DCR in CPVT. Importantly, the antiarrhythmic effects of flecainide can be attributed, at least in part, to its nNa v blocking properties.

scholarly journals Calcium homeostasis in a local/global whole cell model of permeabilized ventricular myocytes with a Langevin description of stochastic calcium release

2015 ◽  
Vol 308 (5) ◽  
pp. H510-H523 ◽  
Author(s):  
Xiao Wang ◽  
Seth H. Weinberg ◽  
Yan Hao ◽  
Eric A. Sobie ◽  
Gregory D. Smith
Keyword(s):  
Calcium Release ◽  
Ventricular Myocytes ◽  
Cell Model ◽  
Ryanodine Receptors ◽  
Planck Equation ◽  
Linear Increase ◽  
Langevin Equations ◽  
Cell Models ◽  
Whole Cell ◽  
Alternative Approach

Population density approaches to modeling local control of Ca2+-induced Ca2+ release in cardiac myocytes can be used to construct minimal whole cell models that accurately represent heterogeneous local Ca2+ signals. Unfortunately, the computational complexity of such “local/global” whole cell models scales with the number of Ca2+ release unit (CaRU) states, which is a rapidly increasing function of the number of ryanodine receptors (RyRs) per CaRU. Here we present an alternative approach based on a Langevin description of the collective gating of RyRs coupled by local Ca2+ concentration ([Ca2+]). The computational efficiency of this approach no longer depends on the number of RyRs per CaRU. When the RyR model is minimal, Langevin equations may be replaced by a single Fokker-Planck equation, yielding an extremely compact and efficient local/global whole cell model that reproduces and helps interpret recent experiments that investigate Ca2+ homeostasis in permeabilized ventricular myocytes. Our calculations show that elevated myoplasmic [Ca2+] promotes elevated network sarcoplasmic reticulum (SR) [Ca2+] via SR Ca2+-ATPase-mediated Ca2+ uptake. However, elevated myoplasmic [Ca2+] may also activate RyRs and promote stochastic SR Ca2+ release, which can in turn decrease SR [Ca2+]. Increasing myoplasmic [Ca2+] results in an exponential increase in spark-mediated release and a linear increase in nonspark-mediated release, consistent with recent experiments. The model exhibits two steady-state release fluxes for the same network SR [Ca2+] depending on whether myoplasmic [Ca2+] is low or high. In the later case, spontaneous release decreases SR [Ca2+] in a manner that maintains robust Ca2+ sparks.

scholarly journals Phosphorylation-Dependent Regulation of Ryanodine Receptors

2001 ◽  
Vol 153 (4) ◽  
pp. 699-708 ◽  
Author(s):  
Steven O. Marx ◽  
Steven Reiken ◽  
Yuji Hisamatsu ◽  
Marta Gaburjakova ◽  
Jana Gaburjakova ◽  
...  
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Rapid Identification ◽  
Calcium Release Channels ◽  
Macromolecular Complexes ◽  
Protein Binding Sites ◽  
Skeletal Muscle Contraction

Ryanodine receptors (RyRs), intracellular calcium release channels required for cardiac and skeletal muscle contraction, are macromolecular complexes that include kinases and phosphatases. Phosphorylation/dephosphorylation plays a key role in regulating the function of many ion channels, including RyRs. However, the mechanism by which kinases and phosphatases are targeted to ion channels is not well understood. We have identified a novel mechanism involved in the formation of ion channel macromolecular complexes: kinase and phosphatase targeting proteins binding to ion channels via leucine/isoleucine zipper (LZ) motifs. Activation of kinases and phosphatases bound to RyR2 via LZs regulates phosphorylation of the channel, and disruption of kinase binding via LZ motifs prevents phosphorylation of RyR2. Elucidation of this new role for LZs in ion channel macromolecular complexes now permits: (a) rapid mapping of kinase and phosphatase targeting protein binding sites on ion channels; (b) predicting which kinases and phosphatases are likely to regulate a given ion channel; (c) rapid identification of novel kinase and phosphatase targeting proteins; and (d) tools for dissecting the role of kinases and phosphatases as modulators of ion channel function.

CaM kinase augments cardiac L-type Ca2+ current: a cellular mechanism for long Q-T arrhythmias

1999 ◽  
Vol 276 (6) ◽  
pp. H2168-H2178 ◽  
Author(s):  
Yuejin Wu ◽  
Leigh B. MacMillan ◽  
R. Blair McNeill ◽  
Roger J. Colbran ◽  
Mark E. Anderson
Keyword(s):  
Ventricular Myocytes ◽  
Ryanodine Receptors ◽  
Cam Kinase ◽  
Early Afterdepolarizations ◽  
Ultrastructural Studies ◽  
Intracellular Ca ◽  
Dependent Protein ◽  
T Tubules ◽  
Rabbit Ventricular Myocytes

Early afterdepolarizations (EAD) caused by L-type Ca2+ current ( I Ca,L) are thought to initiate long Q-T arrhythmias, but the role of intracellular Ca2+ in these arrhythmias is controversial. Rabbit ventricular myocytes were stimulated with a prolonged EAD-containing action potential-clamp waveform to investigate the role of Ca2+/calmodulin-dependent protein kinase II (CaM kinase) in I Ca,L during repolarization. I Ca,L was initially augmented, and augmentation was dependent on Ca2+ from the sarcoplasmic reticulum because the augmentation was prevented by ryanodine or thapsigargin. I Ca,Laugmentation was also dependent on CaM kinase, because it was prevented by dialysis with the inhibitor peptide AC3-I and reconstituted by exogenous constitutively active CaM kinase when Ba2+ was substituted for bath Ca2+. Ultrastructural studies confirmed that endogenous CaM kinase, L-type Ca2+ channels, and ryanodine receptors colocalized near T tubules. EAD induction was significantly reduced in current-clamped cells dialyzed with AC3-I (4/15) compared with cells dialyzed with an inactive control peptide (11/15, P = 0.013). These findings support the hypothesis that EADs are facilitated by CaM kinase.

scholarly journals A Simplified Local Control Model of Calcium-Induced Calcium Release in Cardiac Ventricular Myocytes

2004 ◽  
Vol 87 (6) ◽  
pp. 3723-3736 ◽  
Author(s):  
R. Hinch ◽  
J.L. Greenstein ◽  
A.J. Tanskanen ◽  
L. Xu ◽  
R.L. Winslow
Keyword(s):  
Local Control ◽  
Calcium Release ◽  
Ventricular Myocytes ◽  
Control Model ◽  
Calcium Induced Calcium Release ◽  
Cardiac Ventricular Myocytes

scholarly journals RYR2 Proteins Contribute to the Formation of Ca2+ Sparks in Smooth Muscle

2004 ◽  
Vol 123 (4) ◽  
pp. 377-386 ◽  
Author(s):  
Guangju Ji ◽  
Morris E. Feldman ◽  
Kai Su Greene ◽  
Vincenzo Sorrentino ◽  
Hong-Bo Xin ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Wild Type ◽  
Calcium Dependent ◽  
Outward Currents ◽  
Associated Proteins ◽  
Kinetics Of ◽  
Spontaneous Transient Outward Currents

Calcium release through ryanodine receptors (RYR) activates calcium-dependent membrane conductances and plays an important role in excitation-contraction coupling in smooth muscle. The specific RYR isoforms associated with this release in smooth muscle, and the role of RYR-associated proteins such as FK506 binding proteins (FKBPs), has not been clearly established, however. FKBP12.6 proteins interact with RYR2 Ca2+ release channels and the absence of these proteins predictably alters the amplitude and kinetics of RYR2 unitary Ca2+ release events (Ca2+ sparks). To evaluate the role of specific RYR2 and FBKP12.6 proteins in Ca2+ release processes in smooth muscle, we compared spontaneous transient outward currents (STOCs), Ca2+ sparks, Ca2+-induced Ca2+ release, and Ca2+ waves in smooth muscle cells freshly isolated from wild-type, FKBP12.6−/−, and RYR3−/− mouse bladders. Consistent with a role of FKBP12.6 and RYR2 proteins in spontaneous Ca2+ sparks, we show that the frequency, amplitude, and kinetics of spontaneous, transient outward currents (STOCs) and spontaneous Ca2+ sparks are altered in FKBP12.6 deficient myocytes relative to wild-type and RYR3 null cells, which were not significantly different from each other. Ca2+ -induced Ca2+ release was similarly augmented in FKBP12.6−/−, but not in RYR3 null cells relative to wild-type. Finally, Ca2+ wave speed evoked by CICR was not different in RYR3 cells relative to control, indicating that these proteins are not necessary for normal Ca2+ wave propagation. The effect of FKBP12.6 deletion on the frequency, amplitude, and kinetics of spontaneous and evoked Ca2+ sparks in smooth muscle, and the finding of normal Ca2+ sparks and CICR in RYR3 null mice, indicate that Ca2+ release through RYR2 molecules contributes to the formation of spontaneous and evoked Ca2+ sparks, and associated STOCs, in smooth muscle.

A model of graded calcium release and L-type Ca2+ channel inactivation in cardiac muscle

2004 ◽  
Vol 286 (3) ◽  
pp. H1154-H1169 ◽  
Author(s):  
Vladimir E. Bondarenko ◽  
Glenna C. L. Bett ◽  
Randall L. Rasmusson
Keyword(s):  
Molecular Mechanisms ◽  
Calcium Release ◽  
Ventricular Myocytes ◽  
Ryanodine Receptors ◽  
Quantitative Description ◽  
Channel Current ◽  
Channel Inactivation ◽  
Transmembrane Voltage ◽  
Intracellular Ca ◽  
Junctional Sarcoplasmic Reticulum

We have developed a model of Ca2+ handling in ferret ventricular myocytes. This model includes a novel L-type Ca2+ channel, detailed intracellular Ca2+ movements, and graded Ca2+-induced Ca2+ release (CICR). The model successfully reproduces data from voltage-clamp experiments, including voltage- and time-dependent changes in intracellular Ca2+ concentration ([Ca2+]i), L-type Ca2+ channel current ( ICaL) inactivation and recovery kinetics, and Ca2+ sparks. The development of graded CICR is critically dependent on spatial heterogeneity and the physical arrangement of calcium channels in opposition to ryanodine-sensitive release channels. The model contains spatially distinct subsystems representing the subsarcolemmal regions where the junctional sarcoplasmic reticulum (SR) abuts the T-tubular membrane and where the L-type Ca2+ channels and SR ryanodine receptors (RyRs) are localized. There are eight different types of subsystems in our model, with between one and eight L-type Ca2+ channels distributed binomially. This model exhibits graded CICR and provides a quantitative description of Ca2+ dynamics not requiring Monte-Carlo simulations. Activation of RyRs and release of Ca2+ from the SR depend critically on Ca2+ entry through L-type Ca2+ channels. In turn, Ca2+ channel inactivation is critically dependent on the release of stored intracellular Ca2+. Inactivation of ICaL depends on both transmembrane voltage and local [Ca2+]i near the channel, which results in distinctive inactivation properties. The molecular mechanisms underlying many ICaL gating properties are unclear, but [Ca2+]i dynamics clearly play a fundamental role.

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