scholarly journals Caspofungin Modulates Ryanodine Receptor-Mediated Calcium Release in Human Cardiac Myocytes

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Christian Koch ◽  
Jennifer Jersch ◽  
Emmanuel Schneck ◽  
Fabian Edinger ◽  
Hagen Maxeiner ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Critically Ill ◽  
Ryanodine Receptor ◽  
Critically Ill Patients ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Intracellular Ca ◽  
Hemodynamic Impairment ◽  
Dose Dependent Increase ◽  
Dose Dependent

ABSTRACT Recent studies showed that critically ill patients might be at risk for hemodynamic impairment during caspofungin (CAS) therapy. The aim of our present study was to examine the mechanisms behind CAS-induced cardiac alterations. We revealed a dose-dependent increase in intracellular Ca2+ concentration ([Ca2+]i) after CAS treatment. Ca2+ ions were found to be released from intracellular caffeine-sensitive stores, most probably via the activation of ryanodine receptors.

Ryanodine Receptor Calcium Release Channels

2002 ◽  
Vol 82 (4) ◽  
pp. 893-922 ◽  
Author(s):  
Michael Fill ◽  
Julio A. Copello
Keyword(s):  
Ryanodine Receptor ◽  
Calcium Release ◽  
Striated Muscle ◽  
Ryanodine Receptors ◽  
Large Body ◽  
Future Directions ◽  
Calcium Release Channels ◽  
Coupling Process ◽  
Contraction Coupling ◽  
Intracellular Ca

The ryanodine receptors (RyRs) are a family of Ca2+ release channels found on intracellular Ca2+ storage/release organelles. The RyR channels are ubiquitously expressed in many types of cells and participate in a variety of important Ca2+ signaling phenomena (neurotransmission, secretion, etc.). In striated muscle, the RyR channels represent the primary pathway for Ca2+ release during the excitation-contraction coupling process. In general, the signals that activate the RyR channels are known (e.g., sarcolemmal Ca2+ influx or depolarization), but the specific mechanisms involved are still being debated. The signals that modulate and/or turn off the RyR channels remain ambiguous and the mechanisms involved unclear. Over the last decade, studies of RyR-mediated Ca2+ release have taken many forms and have steadily advanced our knowledge. This robust field, however, is not without controversial ideas and contradictory results. Controversies surrounding the complex Ca2+ regulation of single RyR channels receive particular attention here. In addition, a large body of information is synthesized into a focused perspective of single RyR channel function. The present status of the single RyR channel field and its likely future directions are also discussed.

Evaluation of Dexmedetomidine Dosing in Obese Critically Ill Patients

2021 ◽  
pp. 089719002110215
Author(s):  
Sara A. Atyia ◽  
Keaton S. Smetana ◽  
Minh C. Tong ◽  
Molly J. Thompson ◽  
Kari M. Cape ◽  
...  
Keyword(s):  
Body Weight ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Statistical Difference ◽  
Ideal Body Weight ◽  
Weight Percentage ◽  
Before And After ◽  
Light Sedation ◽  
Icu Sedation ◽  
Dose Dependent

Background: Dexmedetomidine is a highly selective α2-adrenoreceptor agonist that produces dose-dependent sedation, anxiolysis, and analgesia without respiratory depression. Due to these ideal sedative properties, there has been increased interest in utilizing dexmedetomidine as a first-line sedative for critically ill patients requiring light sedation. Objective: To evaluate the ability to achieve goal intensive care unit (ICU) sedation before and after an institutional change of dosing from actual (ABW) to adjusted (AdjBW) body weight in obese patients on dexmedetomidine. Methods: This study included patients ≥ 18 years old, admitted to a surgical or medical ICU, required dexmedetomidine for at least 8 hours as a single continuous infusion sedative, and weighed ≥ 120% of ideal body weight. Percentage of RASS measurements within goal range (−1 to +1) during the first 48 hours after initiation of dexmedetomidine as the sole sedative agent or until discontinuation dosed on ABW compared to AdjBW was evaluated. Results: 100 patients were included in the ABW cohort and 100 in the AdjBW cohort. The median dosing weight was significantly higher in the ABW group (95.9 [78.9-119.5] vs 82.2 [72.1-89.8] kg; p = 0.001). There was no statistical difference in percent of RASS measurements in goal range (61.5% vs 69.6%, p = 0.267) in patients that received dexmedetomidine dosed based on ABW versus AdjBW. Conclusion: Dosing dexmedetomidine using AdjBW in obese critically ill patients for ongoing ICU sedation resulted in no statistical difference in the percent of RASS measurements within goal when compared to ABW dosing. Further studies are warranted.

scholarly journals Sex-related effects on diabetes-induced alterations in calcium release in the rat heart

2007 ◽  
Vol 293 (6) ◽  
pp. H3584-H3592 ◽  
Author(s):  
Nazmi Yaras ◽  
Erkan Tuncay ◽  
Nuhan Purali ◽  
Babur Sahinoglu ◽  
Guy Vassort ◽  
...  
Keyword(s):  
Calcium Release ◽  
Binding Protein ◽  
Ryanodine Receptors ◽  
Left Ventricular ◽  
Adult Rats ◽  
Fk506 Binding Protein ◽  
Pressure Development ◽  
Spatiotemporal Parameters ◽  
Intracellular Ca ◽  
Developed Pressure

The present study was designed to determine whether the properties of local Ca2+ release and its related regulatory mechanisms might provide insight into the role of sex differences in heart functions of control and streptozotocin-induced diabetic adult rats. Left ventricular developed pressure, the rates of pressure development and decay (±dP/d t), basal intracellular Ca2+ level ([Ca2+]i), and spatiotemporal parameters of [Ca2+]i transients were found to be similar in male and female control rats. However, spatiotemporal parameters of Ca2+ sparks in cardiomyocytes isolated from control females were significantly larger and slower than those in control males. Diabetes reduced left ventricular developed pressure to a lower extent in females than in males, and the diabetes-induced depressions in both +dP/d t and −dP/d t were less in females than in males. Diabetes elicited a smaller reduction in the amplitude of [Ca2+]i transients in females than in males, a smaller reduction in sarcoplasmic reticulum-Ca2+ load, and less increase in basal [Ca2+]i. Similarly, the elementary Ca2+ events and their control proteins were clearly different in both sexes, and these differences were more marked in diabetes. Diabetes-induced depression of the Ca2+ spark amplitude was significantly less in females than in matched males. Levels of cardiac ryanodine receptors (RyR2) and FK506-binding protein 12.6 in control females were significantly higher than those shown in control males. Diabetes induced less RyR2 phosphorylation and FK506-binding protein 12.6 unbinding in females. Moreover, total and free sulfhydryl groups were significantly less reduced, and PKC levels were less increased, in diabetic females than in diabetic males. The present data related to local Ca2+ release and its related proteins describe some of the mechanisms that may underlie sex-related differences accounting for females to have less frequent development of cardiac diseases.

scholarly journals Cardiac Effects of Echinocandins in Endotoxemic Rats

2015 ◽  
Vol 60 (1) ◽  
pp. 301-306 ◽  
Author(s):  
Christian Koch ◽  
Matthias Wolff ◽  
Michael Henrich ◽  
Markus A. Weigand ◽  
Christoph Lichtenstern ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Fungal Infections ◽  
Underlying Mechanism ◽  
Rank Test ◽  
Control Group ◽  
Endotoxemic Shock ◽  
And Control ◽  
Dose Dependent Increase ◽  
Dose Dependent

ABSTRACTEchinocandins are known as effective and safe agents for the prophylaxis and treatment of different cohorts of patients with fungal infections. Recent studies revealed that certain pharmacokinetics of echinocandin antifungals might impact clinical efficacy and safety in special patient populations. The aim of our study was to evaluate echinocandin-induced aggravation of cardiac impairment in septic shock. Using anin vivoendotoxemic shock model in rats, we assessed hemodynamic parameters and time to hemodynamic failure (THF) after additional central-venous application of anidulafungin (2.5 mg/kg of body weight [BW]), caspofungin (0.875 mg/kg BW), micafungin (3 mg/kg BW), and control (0.9% sodium chloride). In addition, echinocandin-induced cytotoxicity was evaluated in isolated rat cardiac myocytes. THF of the animals in the caspofungin group (n= 7) was significantly reduced compared to that in the control (n= 6) (136 min versus 180 min;P= 0.0209). The anidulafungin group (n= 7) also showed a trend of reduced THF (136 min versus 180 min; log-rank testP= 0.0578). Animals in the micafungin group (n= 7) did not show significant differences in THF compared to those in the control. Control group animals and also micafungin group animals did not show altered cardiac output (CO) during our experiments. In contrast, administration of anidulafungin or caspofungin induced a decrease in CO. We also revealed a dose-dependent increase of cytotoxicity in anidulafungin- and caspofungin-treated cardiac myocytes. Treatment with micafungin did not cause significantly increased cytotoxicity. Further studies are needed to explore the underlying mechanism.

scholarly journals Akkermansia muciniphila secretome promotes α-synuclein aggregation in enteroendocrine cells

2021 ◽  
Author(s):  
Dionísio Pedro Amorim Neto ◽  
Beatriz Pelegrini Bosque ◽  
João Vitor Pereira de Godoy ◽  
Paulla Vieira Rodrigues ◽  
Dario Donoso Meneses ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Enteroendocrine Cells ◽  
Ros Generation ◽  
List Type ◽  
Functional Link ◽  
Akkermansia Muciniphila ◽  
Intracellular Ca

ABSTRACTThe notion that the gut microbiota play a role in neurodevelopment, behavior and outcome of neurodegenerative disorders is recently taking place. A number of studies have consistently reported a greater abundance of Akkermansia muciniphila in Parkinson’s disease (PD) fecal samples. Nevertheless, a functional link between A.muciniphila and sporadic PD remained unexplored. Here, we investigated whether A.muciniphila secretome could initiate the misfolding process of α-synuclein (αSyn) in enteroendocrine cells (EECs), which are part of the gut epithelium and possess many neuron-like properties. We found that A.muciniphila secretome is directly modulated by mucin, induces intracellular calcium (Ca2+) release, and causes increased mitochondrial Ca2+ uptake in EECs, which in turn leads to production of reactive oxygen species (ROS) and αSyn aggregation. However, these events were efficiently inhibited once we buffered mitochondrial Ca2+. Thereby, these molecular insights provided here offer evidence that bacterial secretome is capable of inducing αSyn aggregation in enteroendocrine cells.SYNOPSIS FIGURE DESCRIPTIONThe secretome isolated from the commensal gut bacterium Akkermansia muciniphila triggers intracellular Ca2+ signaling in enteroendocrine cells, leading to increased mitochondrial Ca2+ uptake. Mitochondrial Ca2+ overload leads to ROS generation culminating with αSyn phosphorylation and aggregation (left panel). All these events were inhibited once mitochondrial Ca2+ is buffered (right panel).Gram-negative gut bacterium Akkermansia muciniphila is consistently found more abundant in Parkinson’s disease patients.Akkermansia muciniphila protein secretome composition is directly modulated by mucin and induces an IP3-independent endoplasmic reticulum (ER)-calcium release in enteroendocrine cells.This Ca2+ release is triggered by direct activation of Ryanodine Receptors leading to increased mitochondrial Ca2+ uptake.Mitochondrial Ca2+ overload leads to ROS generation culminating with αSyn aggregation.Buffering mitochondrial Ca2+ efficiently inhibits A.muciniphila-induced αSyn aggregation in enteroendocrine cells.

Adaptation of the skeletal muscle calcium-release mechanism to weight-bearing condition

1996 ◽  
Vol 270 (6) ◽  
pp. C1588-C1594 ◽  
Author(s):  
S. C. Kandarian ◽  
D. G. Peters ◽  
T. G. Favero ◽  
C. W. Ward ◽  
J. H. Williams
Keyword(s):  
Ryanodine Receptor ◽  
Calcium Release ◽  
Binding Capacity ◽  
Polyclonal Antibodies ◽  
Weight Bearing ◽  
Ryanodine Receptors ◽  
Release Mechanism ◽  
Surgical Removal ◽  
Scatchard Analysis ◽  
Western Blots

In the present study, we examined whether weight-bearing condition can regulate the sarcoplasmic reticulum (SR) Ca(2+)-release mechanism. Measurements of alpha 1-subunit dihydropyridine (alpha 1-DHP) and ryanodine receptor levels were made in hypertrophied fast-twitch plantaris muscles 5 wk after surgical removal of synergist muscles (increased weight bearing) and in atrophied slowtwitch soleus muscles (14 days of non-weight bearing) of the rat. Rates of AgNO3-induced SR Ca2+ release were measured with fura 2 as the Ca2+ indicator and pyrophosphate as the precipitating ion during vesicular Ca2+ loading. Ca(2+)-release rates were 38, 49, and 58% lower in vesicles from hypertrophied vs. control muscles at AgNO3 concentrations of 0.05, 0.5, and 5 microM, respectively (control = 18.2 +/- 1.4 microM.mg-1. min-1). Western blots showed no differences in the relative expression of alpha 1-DHP or ryanodine receptor when IIID5 (monoclonal) or GP3 (polyclonal) antibodies were used. There was also no difference in ryanodine (10 nM) binding in Ca(2+)-incubated SR vesicles from hypertrophied muscles, suggesting no difference in the number of channels. In contrast, expression of alpha 1-DHP and ryanodine receptors was increased by 144 and 157% in non-weight-bearing soleus muscles, respectively. Scatchard analysis of DHP binding showed a 40% increase in maximum binding capacity and no change in the dissociation constant with non-weight-bearing muscles. The direction of modification of the SR Ca(2+)-release mechanism is opposite with increased and decreased weight bearing, but the mechanism by which this is achieved appears to be different.

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.

Involvement of the Ryanodine Receptor in Morphologic Modification of Hermissenda Type B Photoreceptors After In Vitro Conditioning

2004 ◽  
Vol 91 (2) ◽  
pp. 728-735 ◽  
Author(s):  
Ryo Kawai ◽  
Tetsuro Horikoshi ◽  
Manabu Sakakibara
Keyword(s):  
Ryanodine Receptor ◽  
Hair Cells ◽  
Ryanodine Receptors ◽  
Terminal Branch ◽  
Type B ◽  
Axon Terminals ◽  
Calcium Chelation ◽  
Intracellular Ca ◽  
Receptor Blockers

We examined whether Ca2+ induced Ca2+ release through ryanodine receptors is involved in the conditioning of specific morphologic changes at the axon terminals of type B photoreceptors in the isolated circumesophageal ganglion of Hermissenda. Calcium chelation by bis(2-aminophenoxy) ethane- N,N,N′, N′-tetraacetic acid prevented the conformational change at the terminals after five paired presentations of light and vibration, which produce terminal branch contraction of B photoreceptors. Two ryanodine receptor blockers, dantrolene and micromolar concentrations of ryanodine, depressed the increase in excitability due to in vitro conditioning and the increase in intracellular Ca2+ in response to membrane depolarization. Although the ability to increase intracellular Ca2+ was depressed, synaptic transmission was preserved in the normal state from hair cells under dantrolene and ryanodine incubation. Ryanodine receptor blockers also prevented contraction at the B photoreceptor axon terminals. These results suggest that the ryanodine receptor has a crucial role in inducing the in vitro conditioning specific changes both physiologically and morphologically, including “focusing” at the B photoreceptor axon terminal.

scholarly journals Cluster of Differentiation 38 (CD38) Mediates Bile Acid-induced Acinar Cell Injury and Pancreatitis through Cyclic ADP-ribose and Intracellular Calcium Release

2013 ◽  
Vol 288 (38) ◽  
pp. 27128-27137 ◽  
Author(s):  
Abrahim I. Orabi ◽  
Kamaldeen A. Muili ◽  
Tanveer A. Javed ◽  
Shunqian Jin ◽  
Thottala Jayaraman ◽  
...  
Keyword(s):  
Bile Acid ◽  
Ryanodine Receptor ◽  
Acinar Cell ◽  
Calcium Release ◽  
Cell Injury ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Iodide Uptake ◽  
Cyclic Adp Ribose ◽  
Intracellular Ca

Aberrant Ca2+ signals within pancreatic acinar cells are an early and critical feature in acute pancreatitis, yet it is unclear how these signals are generated. An important mediator of the aberrant Ca2+ signals due to bile acid exposure is the intracellular Ca2+ channel ryanodine receptor. One putative activator of the ryanodine receptor is the nucleotide second messenger cyclic ADP-ribose (cADPR), which is generated by an ectoenzyme ADP-ribosyl cyclase, CD38. In this study, we examined the role of CD38 and cADPR in acinar cell Ca2+ signals and acinar injury due to bile acids using pharmacologic inhibitors of CD38 and cADPR as well as mice deficient in Cd38 (Cd38−/−). Cytosolic Ca2+ signals were imaged using live time-lapse confocal microscopy in freshly isolated mouse acinar cells during perifusion with the bile acid taurolithocholic acid 3-sulfate (TLCS; 500 μm). To focus on intracellular Ca2+ release and to specifically exclude Ca2+ influx, cells were perifused in Ca2+-free medium. Cell injury was assessed by lactate dehydrogenase leakage and propidium iodide uptake. Pretreatment with either nicotinamide (20 mm) or the cADPR antagonist 8-Br-cADPR (30 μm) abrogated TLCS-induced Ca2+ signals and cell injury. TLCS-induced Ca2+ release and cell injury were reduced by 30 and 95%, respectively, in Cd38-deficient acinar cells compared with wild-type cells (p < 0.05). Cd38-deficient mice were protected against a model of bile acid infusion pancreatitis. In summary, these data indicate that CD38-cADPR mediates bile acid-induced pancreatitis and acinar cell injury through aberrant intracellular Ca2+ signaling.

Intracellular Calcium Plays a Critical Role in the Microcystin-LR-Elicited Neurotoxicity Through PLC/IP3 Pathway

2015 ◽  
Vol 34 (6) ◽  
pp. 551-558 ◽  
Author(s):  
Fei Cai ◽  
Jue Liu ◽  
Cairong Li ◽  
Jianghua Wang
Keyword(s):  
Hippocampal Neurons ◽  
Critical Role ◽  
Free Calcium ◽  
Intracellular Ca ◽  
Intracellular Free Calcium Concentration ◽  
Free Calcium Concentration ◽  
Free Media ◽  
Trisphosphate Receptor ◽  
Dose Dependent Increase ◽  
Dose Dependent

Neurotoxicity of microcystin-leucine-arginine (MCLR) has been widely reported. However, the mechanism is not fully understood. Using primary hippocampal neurons, we tested the hypothesis that MCLR-triggered activation in intracellular free calcium concentration ([Ca2+]i) induces the death of neurons. Microcystin-leucine-arginine inhibited cell viability at a range of 0.1 to 30 μmol/L and caused a dose-dependent increase in [Ca2+]i. This increase in [Ca2+]i was observed in Ca2+-free media and blocked by an endoplasmic reticulum Ca2+ pump inhibitor, suggesting intracellular Ca2+ release. Moreover, pretreatment of hippocampal neurons with intracellular Ca2+ chelator (O,O′-bis (2-aminophenyl) ethyleneglycol-N,N,N′,N′-tetraacetic acid, tetraacetoxy-methyl ester) and inositol 1,4,5-trisphosphate receptor antagonist (2-aminoethoxydiphenyl borate) could block both the Ca2+ mobilization and the neuronal death following MCLR exposure. In contrast, the ryanodine receptor inhibitor (dantrolene) did not ameliorate the effect of MCLR. In conclusion, MCLR disrupts [Ca2+]i homeostasis in neurons by releasing Ca2+ from intracellular stores, and this increase in [Ca2+]i may be a key determinant in the mechanism underlying MCLR-induced neurotoxicity.

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