scholarly journals Spontaneous Ca2+ sparks and Ca2+ homeostasis in a minimal model of permeabilized ventricular myocytes

2010 ◽  
Vol 299 (6) ◽  
pp. H1996-H2008 ◽  
Author(s):  
Jana M. Hartman ◽  
Eric A. Sobie ◽  
Gregory D. Smith
Keyword(s):  
Dwell Time ◽  
Ventricular Myocytes ◽  
Molecular Level ◽  
Cell Model ◽  
Ryanodine Receptors ◽  
Low Frequency ◽  
Open Probability ◽  
Long Duration ◽  
Release Flux ◽  
Health And Disease

Many issues remain unresolved concerning how local, subcellular Ca2+ signals interact with bulk cellular concentrations to maintain homeostasis in health and disease. To aid in the interpretation of data obtained in quiescent ventricular myocytes, we present here a minimal whole cell model that accounts for both localized (subcellular) and global (cellular) aspects of Ca2+ signaling. Using a minimal formulation of the distribution of local [Ca2+] associated with a large number of Ca2+-release sites, the model simulates both random spontaneous Ca2+ sparks and the changes in myoplasmic and sarcoplasmic reticulum (SR) [Ca2+] that result from the balance between stochastic release and reuptake into the SR. Ca2+-release sites are composed of clusters of two-state ryanodine receptors (RyRs) that exhibit activation by local cytosolic [Ca2+] but no inactivation or regulation by luminal Ca2+. Decreasing RyR open probability in the model causes a decrease in aggregate release flux and an increase in SR [Ca2+], regardless of whether RyR inhibition is mediated by a decrease in RyR open dwell time or an increase in RyR closed dwell time. The same balance of stochastic release and reuptake can be achieved, however, by either high-frequency/short-duration or low-frequency/long-duration Ca2+ sparks. The results are well correlated with recent experimental observations using pharmacological RyR inhibitors and clarify those aspects of the release-reuptake balance that are inherent to the coupling between local and global Ca2+ signals and those aspects that depend on molecular-level details. The model of Ca2+ sparks and homeostasis presented here can be a useful tool for understanding changes in cardiac Ca2+ release resulting from drugs, mutations, or acquired diseases.

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 Junctophilin-2 tethers T-tubules and recruits functional L-type calcium channels to lipid rafts in adult cardiomyocytes

2020 ◽  
Author(s):  
Claire Poulet ◽  
Jose Sanchez-Alonso ◽  
Pamela Swiatlowska ◽  
Florence Mouy ◽  
Carla Lucarelli ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Lipid Rafts ◽  
Ventricular Myocytes ◽  
Ryanodine Receptors ◽  
Calcium Signalling ◽  
Super Resolution ◽  
Scaffolding Protein ◽  
Open Probability ◽  
T Tubules ◽  
Membrane Treatment

Abstract Aim In cardiomyocytes, transverse tubules (T-tubules) associate with the sarcoplasmic reticulum (SR), forming junctional membrane complexes (JMCs) where L-type calcium channels (LTCCs) are juxtaposed to Ryanodine receptors (RyR). Junctophilin-2 (JPH2) supports the assembly of JMCs by tethering T-tubules to the SR membrane. T-tubule remodelling in cardiac diseases is associated with downregulation of JPH2 expression suggesting that JPH2 plays a crucial role in T-tubule stability. Furthermore, increasing evidence indicate that JPH2 might additionally act as a modulator of calcium signalling by directly regulating RyR and LTCCs. This study aimed at determining whether JPH2 overexpression restores normal T-tubule structure and LTCC function in cultured cardiomyocytes. Methods and results Rat ventricular myocytes kept in culture for 4 days showed extensive T-tubule remodelling with impaired JPH2 localization and relocation of the scaffolding protein Caveolin3 (Cav3) from the T-tubules to the outer membrane. Overexpression of JPH2 restored T-tubule structure and Cav3 relocation. Depletion of membrane cholesterol by chronic treatment with methyl-β-cyclodextrin (MβCD) countered the stabilizing effect of JPH2 overexpression on T-tubules and Cav3. Super-resolution scanning patch-clamp showed that JPH2 overexpression greatly increased the number of functional LTCCs at the plasma membrane. Treatment with MβCD reduced LTCC open probability and activity. Proximity ligation assays showed that MβCD did not affect JPH2 interaction with RyR and the pore-forming LTCC subunit Cav1.2, but strongly impaired JPH2 association with Cav3 and the accessory LTCC subunit Cavβ2. Conclusions JPH2 promotes T-tubule structural stability and recruits functional LTCCs to the membrane, most likely by directly binding to the channel. Cholesterol is involved in the binding of JPH2 to T-tubules as well as in the modulation of LTCC activity. We propose a model where cholesterol and Cav3 support the assembly of lipid rafts which provide an anchor for JPH2 to form JMCs and a platform for signalling complexes to regulate LTCC activity.

Mechanisms of excitation-contraction uncoupling relevant to activity-induced muscle fatigueThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 34 (3) ◽  
pp. 368-372 ◽  
Author(s):  
Graham D. Lamb
Keyword(s):  
Structural Changes ◽  
Peer Review Process ◽  
Ryanodine Receptors ◽  
Low Frequency ◽  
Force Production ◽  
Dihydropyridine Receptors ◽  
Long Duration ◽  
Triad Junction ◽  
Sensor Molecules ◽  
Selection Of

If the free [Ca2+] in the cytoplasm of a skeletal muscle fiber is raised substantially for a period of seconds to minutes or to high levels just briefly, it leads to disruption of the normal excitation-contraction (E-C) coupling process and a consequent long-lasting decrease in force production. It appears that the disruption to the coupling occurs at the triad junction, where the voltage-sensor molecules (dihydropyridine receptors) normally interact with and open the Ca2+ release channels (ryanodine receptors) in the adjacent sarcoplasmic reticulum (SR). This disruption results in inadequate release of SR Ca2+ upon stimulation. Such E-C uncoupling may underlie the long-duration low-frequency fatigue that can occur after various types of exercise, as well as possibly being a contributing factor to the muscle weakness in certain muscle diseases. The process or processes causing the disruption of the coupling between the voltage sensors and the release channels is not known with certainty, but might be associated with structural changes at the triad junction, possibly caused by activation of the Ca2+-dependent protease, µ-calpain.

scholarly journals Cardiac small-conductance calcium-activated potassium channels in health and disease

2021 ◽  
Vol 473 (3) ◽  
pp. 477-489 ◽  
Author(s):  
Xiao-Dong Zhang ◽  
Phung N. Thai ◽  
Deborah K. Lieu ◽  
Nipavan Chiamvimonvat
Keyword(s):  
Ventricular Myocytes ◽  
Pulmonary Veins ◽  
Differential Sensitivity ◽  
Sk Channels ◽  
Sk Channel ◽  
Ventricular Cells ◽  
Intracellular Ca ◽  
Life Threatening ◽  
Health And Disease ◽  
Small Conductance

AbstractSmall-conductance Ca2+-activated K+ (SK, KCa2) channels are encoded by KCNN genes, including KCNN1, 2, and 3. The channels play critical roles in the regulation of cardiac excitability and are gated solely by beat-to-beat changes in intracellular Ca2+. The family of SK channels consists of three members with differential sensitivity to apamin. All three isoforms are expressed in human hearts. Studies over the past two decades have provided evidence to substantiate the pivotal roles of SK channels, not only in healthy heart but also with diseases including atrial fibrillation (AF), ventricular arrhythmia, and heart failure (HF). SK channels are prominently expressed in atrial myocytes and pacemaking cells, compared to ventricular cells. However, the channels are significantly upregulated in ventricular myocytes in HF and pulmonary veins in AF models. Interests in cardiac SK channels are further fueled by recent studies suggesting the possible roles of SK channels in human AF. Therefore, SK channel may represent a novel therapeutic target for atrial arrhythmias. Furthermore, SK channel function is significantly altered by human calmodulin (CaM) mutations, linked to life-threatening arrhythmia syndromes. The current review will summarize recent progress in our understanding of cardiac SK channels and the roles of SK channels in the heart in health and disease.

Chemical modification of Ca(2+)-activated potassium channels of GH3 anterior pituitary cells

1992 ◽  
Vol 263 (5) ◽  
pp. C1081-C1087 ◽  
Author(s):  
A. M. Frace ◽  
D. C. Eaton
Keyword(s):  
Single Channel ◽  
Gh3 Cells ◽  
Disulfonic Acid ◽  
State Transitions ◽  
Trinitrobenzene Sulfonic Acid ◽  
Voltage Sensitivity ◽  
Pituitary Cells ◽  
Amino Groups ◽  
Open Probability ◽  
Long Duration

The effects of amino group specific reagents were examined on single, large-conductance, Ca(2+)-activated, K+ channels in excised membrane patches from GH3 cells. The reagents used include trinitrobenzene sulfonic acid, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid and its 4-acetamido derivative, and sulfophenyl-isothiocyanate. These reagents react covalently with peptide terminal amino groups and the epsilon amino groups of lysine residues, thereby removing positive charge. Internal application of 0.1-1.0 mM reagent to inside-out patches irreversibly increases channel open probability. Single-channel conductance and voltage sensitivity are not affected by modification. Analysis of channel openings and closures shows that the increase in open probability is predominantly due to the loss of long-duration closures of the channel; however, the lengths of long-duration openings are increased. After the modification in the presence of Ca2+ was performed, the channel open probability remains large, regardless of the internal Ca2+ concentration. Transitions among several open and closed states of the modified channel are present in the absence of Ca2+, suggesting that many state transitions are not directly dependent on Ca2+ binding or dissociation.

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

Larger late sodium current density as well as greater sensitivities to ATX II and ranolazine in rabbit left atrial than left ventricular myocytes

2014 ◽  
Vol 306 (3) ◽  
pp. H455-H461 ◽  
Author(s):  
Antao Luo ◽  
Jihua Ma ◽  
Yejia Song ◽  
Chunping Qian ◽  
Ying Wu ◽  
...  
Keyword(s):  
Left Atrial ◽  
Ventricular Myocytes ◽  
Sodium Current ◽  
Left Ventricular ◽  
Atrial Myocytes ◽  
Open Probability ◽  
Late Sodium Current ◽  
Ventricular Cells ◽  
Open Time ◽  
Hill Slope

An increase of cardiac late sodium current ( INa.L) is arrhythmogenic in atrial and ventricular tissues, but the densities of INa.L and thus the potential relative contributions of this current to sodium ion (Na+) influx and arrhythmogenesis in atria and ventricles are unclear. In this study, whole-cell and cell-attached patch-clamp techniques were used to measure INa.L in rabbit left atrial and ventricular myocytes under identical conditions. The density of INa.L was 67% greater in left atrial (0.50 ± 0.09 pA/pF, n = 20) than in left ventricular cells (0.30 ± 0.07 pA/pF, n = 27, P < 0.01) when elicited by step pulses from −120 to −20 mV at a rate of 0.2 Hz. Similar results were obtained using step pulses from −90 to −20 mV. Anemone toxin II (ATX II) increased INa.L with an EC50 value of 14 ± 2 nM and a Hill slope of 1.4 ± 0.1 ( n = 9) in atrial myocytes and with an EC50 of 21 ± 5 nM and a Hill slope of 1.2 ± 0.1 ( n = 12) in ventricular myocytes. Na+ channel open probability (but not mean open time) was greater in atrial than in ventricular cells in the absence and presence of ATX II. The INa.L inhibitor ranolazine (3, 6, and 9 μM) reduced INa.L more in atrial than ventricular myocytes in the presence of 40 nM ATX II. In summary, rabbit left atrial myocytes have a greater density of INa.L and higher sensitivities to ATX II and ranolazine than rabbit left ventricular myocytes.

Chronic receptor-mediated activation of Gi/o proteins alters basal t-tubular and sarcolemmal L-type Ca2+ channel activity through phosphatases in heart failure

2012 ◽  
Vol 302 (8) ◽  
pp. H1645-H1654 ◽  
Author(s):  
Toshihide Kashihara ◽  
Tsutomu Nakada ◽  
Hisashi Shimojo ◽  
Miwa Horiuchi-Hirose ◽  
Simmon Gomi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Current Density ◽  
Ventricular Myocytes ◽  
Heterotrimeric G Proteins ◽  
Channel Activity ◽  
Open Probability ◽  
Current Densities ◽  
Fractional Shortening ◽  
Pp2a Inhibitor

L-type Ca2+ channels (LTCCs) play an essential role in the excitation-contraction coupling of ventricular myocytes. We previously found that t-tubular (TT) LTCC current density was halved by the activation of protein phosphatase (PP)1 and/or PP2A, whereas surface sarcolemmal (SS) LTCC current density was increased by the inhibition of PP1 and/or PP2A activity in failing ventricular myocytes of mice chronically treated with isoproterenol (ISO mice). In the present study, we examined the possible involvement of inhibitory heterotrimeric G proteins (Gi/o) in these abnormalities by chronically administrating pertussis toxin (PTX) to ISO mice (ISO + PTX mice). Compared with ISO mice, ISO + PTX mice exhibited significantly higher fractional shortening of the left ventricle. The expression level of Gαi2 proteins was not altered by the treatment of mice with ISO and/or PTX. ISO + PTX myocytes had normal TT and SS LTCC current densities because they had higher and lower availability and/or open probability of TT and SS LTCCs than ISO myocytes, respectively. A selective PKA inhibitor, H-89, did not affect LTCC current densities in ISO + PTX myocytes. A selective PP2A inhibitor, fostriecin, did not affect SS or TT current density in control or ISO + PTX myocytes but significantly increased TT but not SS LTCC current density in ISO myocytes. These results indicate that chronic receptor-mediated activation of Gi/o in vivo decreases basal TT LTCC activity by activating PP2A and increases basal SS LTCC activity by inhibiting PP1 without modulating PKA in heart failure.

Electroacupuncture at Zusanli Rescues the Enteric Neuronal Loss in the Stomach of Diabetic Rats

2012 ◽  
Vol 18 (1) ◽  
pp. 5-14 ◽  
Author(s):  
Min Hu ◽  
Fan Du ◽  
Shi Liu
Keyword(s):  
High Frequency ◽  
Low Frequency ◽  
Neuronal Loss ◽  
Diabetic Rats ◽  
Enteric Neurons ◽  
Control Group ◽  
Sprague Dawley ◽  
Long Duration ◽  
Sprague Dawley Rats ◽  
Zusanli Acupoint

The purpose of this study was to investigate the effects of electroacupuncture at Zusanli acupoint on the enteric neuropathy in diabetic rats. Sprague–Dawley rats were divided into different groups depending on the total electroacupuncture span and frequency. The expression of nitric oxide synthase (nNOS), choline acetyltransferase (CHAT), protein gene product 9.5 (PGP9.5), and doublecortin was significantly decreased in the diabetic group compared with the control group. Long-term electroacupuncture at Zusanli with either high frequency or low frequency could increase the expression levels of nNOS, CHAT, PGP9.5, and doublecortin, and the increase was greater in the high-frequency group. But no obvious changes were seen in the short-term electroacupuncture groups. These results suggest that electroacupuncture at Zusanli can restore the deficiency of enteric neurons in diabetes partly but a comparative long duration of stimuli (6 weeks) is required. The increase of doublecortin may be involved in this positive process.

Abstract 497: Normalization of Intracellular Calcium Signaling by Chronic Cardiac Resynchronization Involves Redox Modulation of Ryanodine Receptors.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Inna Gyorke ◽  
Radmila Terentyeva ◽  
Serge Viatchenko-Karpinski ◽  
Dmitry Terentyev ◽  
Yoshinori Nishijima ◽  
...  
Keyword(s):  
Ryanodine Receptors ◽  
Redox Balance ◽  
Oxidative Modification ◽  
Cardiac Resynchronization ◽  
Open Probability ◽  
Redox Modulation ◽  
Partial Restoration ◽  
Enhanced Sensitivity ◽  
Lv Dysfunction ◽  
Intracellular Calcium Signaling

Cardiac resynchronization therapy (CRT) represents a promising treatment modality to alleviate LV dysfunction in humans with heart failure (HF). Using a canine chronic model of HF, we recently showed that CRT improves abnormal Ca2+ handling by reducing the diastolic Ca2+ leak from the SR through cardiac ryanodine receptors (RyR2s). Using the same models of HF and CRT therapy, we now demonstrate that the specific molecular mechanism for improved RyR2-mediated Ca2+ signaling involves partial restoration of RyR2s from post-translational oxidative modifications. RyR2 expression was markedly reduced in HF and restored to control levels after CRT. Single RyR2 channel activity from HF and CRT groups were recorded using the lipid bilayer technique. In both HF and CRT groups two functional types of RyR2s could be clearly distinguished based on their overall activity as well as sensitivities to luminal ( trans ) Ca2+ and cytosolic ( cis ) Mg2+: high-Po (open probability) and low-Po RyR2s; in contrast to normal controls (only low-Po). High-Po RyR2s in both groups exhibited enhanced sensitivity to trans Ca2+ and increased resistance to inhibition with cis Mg2+. These properties of the high Po RyR2s define the hyperactive, i.e. leaky RyR2 behavior in HF. Low-Po RyR2s had functional properties which did not differ from those observed in RyR2s from normal hearts. In HF ~80% of the RyR2s were high Po, while only ~20% were low Po RyR2s. Following CRT, the fraction of low Po RyR2s increased (to ~60%) while the remainder had high-Po behavior. High-Po channels could be partially normalized by the reducing agent DTT; whereas low-Po channels could be converted to the high Po type by treatment with the oxidative agent DTDP. These results suggest that RyR2 alterations in HF and normalization by CRT occur by redox modulation of a small number of critical sites susceptible to reversible oxidative modification. Additionally, the altered balance of the RyR2 functional fractions following CRT could reflect replacement of irreversibly modified RyR2s by newly synthesized protein, under condition of reduced oxidative stress. These data suggest that altered redox modulation contributes to abnormal function of the RyR2s in HF and that improved RyR2 redox balance may contribute to the efficacy of CRT.

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