Activation of calcium release assessed by calcium release-induced inactivation of calcium current in rat cardiac myocytes

2004 ◽  
Vol 286 (2) ◽  
pp. C330-C341 ◽  
Author(s):  
Alexandra Zahradníková ◽  
Zuzana Kubalová ◽  
Jana Pavelková ◽  
Sándor Györke ◽  
Ivan Zahradník
Keyword(s):  
Cardiac Myocytes ◽  
Lipid Bilayers ◽  
Calcium Current ◽  
Calcium Release ◽  
Flash Photolysis ◽  
Ventricular Myocytes ◽  
Calcium Influx ◽  
Ryanodine Receptors ◽  
Test Pulse ◽  
Dyadic Space

In mammalian cardiac myocytes, calcium released into the dyadic space rapidly inactivates calcium current ( ICa). We used this Ca2+ release-dependent inactivation (RDI) of ICa as a local probe of sarcoplasmic reticulum Ca2+ release activation. In whole cell patch-clamped rat ventricular myocytes, Ca2+ entry induced by short prepulses from —50 mV to positive voltages caused suppression of peak ICa during a test pulse. The negative correlation between peak ICa suppression and ICa inactivation during the test pulse indicated that RDI evoked by the prepulse affected only calcium channels in those dyads in which calcium release was activated. Ca2+ ions injected during the prepulse and during the subsequent tail current suppressed peak ICa in the test pulse to a different extent. Quantitative analysis indicated that equal Ca2+ charge was 3.5 times less effective in inducing release when entering during the prepulse than when entering during the tail. Tail Ca2+ charge injected by the first voltage-dependent calcium channel (DHPR) openings was three times less effective than that injected by DHPR reopenings. These findings suggest that calcium release activation can be profoundly influenced by the recent history of L-type Ca2+ channel activity due to potentiation of ryanodine receptors (RyRs) by previous calcium influx. This conclusion was confirmed at the level of single RyRs in planar lipid bilayers: using flash photolysis of the calcium cage NP-EGTA to generate two sequential calcium stimuli, we showed that RyR activation in response to the second stimulus was four times higher than that in response to the first stimulus.

scholarly journals In silico simulations reveal that RYR distribution affects the dynamics of calcium release in cardiac myocytes

2021 ◽  
Vol 153 (4) ◽  
Author(s):  
Bogdan I. Iaparov ◽  
Ivan Zahradnik ◽  
Alexander S. Moskvin ◽  
Alexandra Zahradníková
Keyword(s):  
Cardiac Myocytes ◽  
In Silico ◽  
Calcium Current ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Physiological Role ◽  
Spatial Arrangement ◽  
Large Set ◽  
Calcium Sparks ◽  
Open Probability

The dyads of cardiac myocytes contain ryanodine receptors (RYRs) that generate calcium sparks upon activation. To test how geometric factors of RYR distribution contribute to the formation of calcium sparks, which cannot be addressed experimentally, we performed in silico simulations on a large set of models of calcium release sites (CRSs). Our models covered the observed range of RYR number, density, and spatial arrangement. The calcium release function of CRSs was modeled by RYR openings, with an open probability dependent on concentrations of free Ca2+ and Mg2+ ions, in a rapidly buffered system, with a constant open RYR calcium current. We found that simulations of spontaneous sparks by repeatedly opening one of the RYRs in a CRS produced three different types of calcium release events (CREs) in any of the models. Transformation of simulated CREs into fluorescence signals yielded calcium sparks with characteristics close to the observed ones. CRE occurrence varied broadly with the spatial distribution of RYRs in the CRS but did not consistently correlate with RYR number, surface density, or calcium current. However, it correlated with RYR coupling strength, defined as the weighted product of RYR vicinity and calcium current, so that CRE characteristics of all models followed the same state-response function. This finding revealed the synergy between structure and function of CRSs in shaping dyad function. Lastly, rearrangements of RYRs simulating hypothetical experiments on splitting and compaction of a dyad revealed an increased propensity to generate spontaneous sparks and an overall increase in calcium release in smaller and more compact dyads, thus underlying the importance and physiological role of RYR arrangement in cardiac myocytes.

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 327: Attenuated Beta-Adrenergic Response in the Tric-a Knock Out Mice

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_2) ◽  
Author(s):  
Yuichi Toyama ◽  
Manabu Yonekura ◽  
Chong Han ◽  
Hirofumi Tomita ◽  
Hiroshi Takeshima ◽  
...  
Keyword(s):  
Heart Rate ◽  
Action Potential ◽  
Sympathetic Nerve ◽  
Calcium Release ◽  
Calcium Influx ◽  
Ryanodine Receptors ◽  
Low Frequency ◽  
Beta Adrenergic ◽  
Knock Out ◽  
Nerve Regulation

Trimeric intracellular cation (TRIC) channels are expressed on the surface of sarcoplasmic reticulum (SR) and regulate calcium release from ryanodine receptors (RyRs). In a previous study, Tric-a knock out (KO) mice showed diminished calcium release from RyRs following increased calcium-influx via L-type calcium channels, which results in enhanced vascular resistance and non-dipper type hypertension. Decreased activation of RyR1 by PKA in skeletal myocytes in Tric-a KO mice is also known. However, physiological importance of TRIC channels on cardiac rhythm formation and its importance on the sympathetic nerve regulation are still obscure. Therefore, we aimed to clarify the effects of Tric-a ablation on cardiac pace making using Tric-a KO mice. We measured systolic blood pressure (SBP) with tail-cuff method, ECG and spontaneous action potential with microelectrode in the Tric-a KO and wild type (WT) mice. Isoproterenol or propranolol was used for sympathetic nerve manipulation. Furthermore, we evaluated heart rate variability (HRV). Tric-a KO mice tended to show limited responses to isoproterenol (0.3 mg/kg) than the WT mice (-27 ± 6 and -32 ± 6 mmHg, n = 10, p =0.70), and to propranolol (4 ± 6 and 13 ± 7 mmHg, n = 5~6, p =0.48). In ECG analysis, ablation of Tric-a gene resulted in significantly decreased heart rate changes to isoproterenol (23 ± 6 and 99 ± 15 bpm, Tric-a KO and WT mice, respectively, n = 9~10, p <0.001). Response to propranolol was also significantly decreased in the Tric-a KO mice (-28 ± 20 and -122 ± 14 bpm, Tric-a KO and WT mice, respectively, n = 9~10, p <0.001). In the action potential recordings, Tric-a KO mice showed significantly decreased sinus rate changes to 1 microM isoproterenol (35 ± 9 and 71 ± 10 bpm, Tric-a KO and WT mice, respectively, n = 6~8, p <0.05). In HRV analysis, low-frequency/high-frequency (LF/HF) ratio tended to be lower in the Tric-a KO mice than the WT mice under the administration of isoproterenol (0.22 ± 0.31 and 0.65 ± 0.16 bpm, Tric-a KO and WT mice, respectively, n = 9~11, p =0.16), suggesting lower sympathetic nerve tonus in the Tric-a KO mice. In conclusion, our data indicates that Tric-a KO mice showed attenuated responses to beta-adrenergic stimulus, which indicates involvement of TRIC-A channels in sympathetic nerve regulation.

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.

Modulation of type-1 Ins(1,4,5)P3 receptor channels by the FK506-binding protein, FKBP12

2002 ◽  
Vol 361 (2) ◽  
pp. 401-407 ◽  
Author(s):  
Sheila L. DARGAN ◽  
Edward J. A. LEA ◽  
Alan P. DAWSON
Keyword(s):  
Lipid Bilayers ◽  
Calcium Release ◽  
Single Channel ◽  
Binding Protein ◽  
Ryanodine Receptors ◽  
Fk506 Binding Protein ◽  
Single Channel Activity ◽  
And Function ◽  
First Time

FK506-binding protein (FKBP12) is highly expressed in neuronal tissue, where it is proposed to localize calcineurin to intracellular calcium-release channels, ryanodine receptors and Ins(1,4,5)P3 receptors (InsP3Rs). The effects of FKBP12 on ryanodine receptors have been well characterized but the nature and function of binding of FKBP12 to InsP3R is more controversial, with evidence for and against a tight interaction between these two proteins. To investigate this, we incorporated purified type-1 InsP3R from rat cerebellum into planar lipid bilayers to monitor the effects of exogenous recombinant FKBP12 on single-channel activity, using K+ as the current carrier. Here we report for the first time that FKBP12 causes a substantial change in single-channel properties of the type-1 InsP3R, specifically to increase the amount of time the channel spends in a fully open state. In the presence of ATP, FKBP12 can also induce co-ordinated gating with neighbouring receptors. The effects of FKBP12 were reversed by FK506. We also present data showing that rapamycin, at sub-optimal concentrations of Ins(2,4,5)P3, decreases the rate of calcium release from cerebellar microsomes. These results provide evidence for a direct functional interaction between FKBP12 and the type-1 InsP3R.

Regulation of calcium release is gated by calcium current, not gating charge, in cardiac myocytes

Science ◽  
1989 ◽  
Vol 244 (4906) ◽  
pp. 800-803 ◽  
Author(s):  
M Nabauer ◽  
G Callewaert ◽  
L Cleemann ◽  
M Morad
Keyword(s):  
Cardiac Myocytes ◽  
Calcium Current ◽  
Calcium Release ◽  
Gating Charge

scholarly journals Large-conductance calcium-activated potassium current modulates excitability in isolated canine intracardiac neurons

2013 ◽  
Vol 304 (3) ◽  
pp. C280-C286 ◽  
Author(s):  
Guillermo J. Pérez ◽  
Mayurika Desai ◽  
Seth Anderson ◽  
Fabiana S. Scornik
Keyword(s):  
Membrane Potential ◽  
Calcium Release ◽  
Single Channel ◽  
Calcium Influx ◽  
Ryanodine Receptors ◽  
Bk Channels ◽  
Release Mechanism ◽  
Dependent Manner ◽  
Whole Cell ◽  
Intracardiac Neurons

We studied principal neurons from canine intracardiac (IC) ganglia to determine whether large-conductance calcium-activated potassium (BK) channels play a role in their excitability. We performed whole cell recordings in voltage- and current-clamp modes to measure ion currents and changes in membrane potential from isolated canine IC neurons. Whole cell currents from these neurons showed fast- and slow-activated outward components. Both current components decreased in the absence of calcium and following 1–2 mM tetraethylammonium (TEA) or paxilline. These results suggest that BK channels underlie these current components. Single-channel analysis showed that BK channels from IC neurons do not inactivate in a time-dependent manner, suggesting that the dynamic of the decay of the fast current component is akin to that of intracellular calcium. Immunohistochemical studies showed that BK channels and type 2 ryanodine receptors are coexpressed in IC principal neurons. We tested whether BK current activation in these neurons occurred via a calcium-induced calcium release mechanism. We found that the outward currents of these neurons were not affected by the calcium depletion of intracellular stores with 10 mM caffeine and 10 μM cyclopiazonic acid. Thus, in canine intracardiac neurons, BK currents are directly activated by calcium influx. Membrane potential changes elicited by long (400 ms) current injections showed a tonic firing response that was decreased by TEA or paxilline. These data strongly suggest that the BK current present in canine intracardiac neurons regulates action potential activity and could increase these neurons excitability.

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.

scholarly journals Calcium influx through If channels in rat ventricular myocytes

2007 ◽  
Vol 292 (3) ◽  
pp. C1147-C1155 ◽  
Author(s):  
Xiao Yu ◽  
Xiao-Wei Chen ◽  
Peng Zhou ◽  
Lijun Yao ◽  
Tao Liu ◽  
...  
Keyword(s):  
Action Potential ◽  
Cardiac Myocytes ◽  
Action Potential Duration ◽  
Channel Blocker ◽  
Ventricular Myocytes ◽  
Spontaneously Hypertensive Rat ◽  
Calcium Influx ◽  
Hek293 Cells ◽  
Hcn Channels ◽  
Rat Ventricular Myocytes

The hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, or cardiac ( If)/neuronal ( Ih) time- and voltage-dependent inward cation current channels, are conventionally considered as monovalent-selective channels. Recently we discovered that calcium ions can permeate through HCN4 and Ih channels in neurons. This raises the possibility of Ca2+ permeation in If, the Ih counterpart in cardiac myocytes, because of their structural homology. We performed simultaneous measurement of fura-2 Ca2+ signals and whole cell currents produced by HCN2 and HCN4 channels (the 2 cardiac isoforms present in ventricles) expressed in HEK293 cells and by If in rat ventricular myocytes. We observed Ca2+ influx when HCN/ If channels were activated. Ca2+ influx was increased with stronger hyperpolarization or longer pulse duration. Cesium, an If channel blocker, inhibited If and Ca2+ influx at the same time. Quantitative analysis revealed that Ca2+ flux contributed to ∼0.5% of current produced by the HCN2 channel or If. The associated increase in Ca2+ influx was also observed in spontaneously hypertensive rat (SHR) myocytes in which If current density is higher than that of normotensive rat ventricle. In the absence of EGTA (a Ca2+ chelator), preactivation of If channels significantly reduced the action potential duration, and the effect was blocked by another selective If channel blocker, ZD-7288. In the presence of EGTA, however, preactivation of If channels had no effects on action potential duration. Our data extend our previous discovery of Ca2+ influx in Ih channels in neurons to If channels in cardiac myocytes.

scholarly journals Synergy of calcium release site determinants in control of calcium release events in cardiac myocytes

2020 ◽  
Author(s):  
B. I. Iaparov ◽  
I. Zahradnik ◽  
A. S. Moskvin ◽  
A. Zahradnikova
Keyword(s):  
Cardiac Myocytes ◽  
Calcium Current ◽  
Calcium Release ◽  
Single Channel ◽  
Release Site ◽  
Mass Action ◽  
Large Set ◽  
Open Probability ◽  
Variable Clustering ◽  
Geometric Factors

AbstractRecent data on structure of dyads in cardiac myocytes indicate variable clustering of RyR calcium release channels. The question arises as to how geometric factors of RyR arrangement translate to their role in formation of calcium release events (CRE). Since this question is not experimentally testable in situ, we performed in silico experiments on a large set of calcium release site (CRS) models. The models covered the range of RyR spatial distributions observed in dyads, and included gating of RyRs with open probability dependent on Ca2+ and Mg2+ concentration. The RyR single-channel calcium current, varied in the range of previously reported values, was set constant in the course of CRE simulations. Other known features of dyads were omitted in the model formulation for clarity. CRE simulations initiated by a single random opening of one of the RyRs in a CRS produced spark-like responses with characteristics that varied with RyR vicinity, a newly defined parameter quantifying spatial distribution of RyRs in the CRSs, and with the RyR single-channel calcium current. The CRE characteristics followed the law of mass action with respect to a CRS state variable, defined as a weighed product of RyR vicinity and RyR single-channel calcium current. The results explained the structure-function relations among determinants of cardiac dyads on synergy principles and thus allowed to evolve the concept of CRS as a dynamic unit of cardiac dyad.

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