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Calcium spark

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https://www.readbyqxmd.com/read/28916340/identification-of-potent-nonabsorbable-agonists-of-the-calcium-sensing-receptor-for-gi-specific-administration
#1
Steven M Sparks, Paul K Spearing, Caroline J Diaz, David J Cowan, Channa Jayawickreme, Grace Chen, Thomas J Rimele, Claudia Generaux, Lindsey T Harston, Shane G Roller
Modulation of gastrointestinal nutrient sensing pathways provides a promising a new approach for the treatment of metabolic diseases including diabetes and obesity. The calcium-sensing receptor has been identified as a key receptor involved in mineral and amino acid nutrient sensing and thus is an attractive target for modulation in the intestine. Herein we describe the optimization of gastrointestinally restricted calcium-sensing receptor agonists starting from a 3-aminopyrrolidine-containing template leading to the identification of GI-restricted agonist 19 (GSK3004774)...
September 7, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28859293/impaired-calcium-homeostasis-is-associated-with-sudden-cardiac-death-and-arrhythmias-in-a-genetic-equivalent-mouse-model-of-the-human-hrc-ser96ala-variant
#2
Christos Tzimas, Daniel M Johnson, Demetrio J Santiago, Elizabeth Vafiadaki, Demetrios A Arvanitis, Constantinos H Davos, Aimilia Varela, Nikolaos C Athanasiadis, Constantinos Dimitriou, Michalis Katsimpoulas, Stephan Sonntag, Mariya Kryzhanovska, Doron Shmerling, Stephan E Lehnart, Karin R Sipido, Evangelia G Kranias, Despina Sanoudou
Aims: The histidine-rich calcium-binding protein (HRC) Ser96Ala variant has previously been identified as a potential biomarker for ventricular arrhythmias and sudden cardiac death in patients with idiopathic dilated cardiomyopathy. Herein, the role of this variant in cardiac pathophysiology is delineated through a novel mouse model, carrying the human mutation in the homologous mouse position. Methods and results: The mouse HRC serine 81, homologous to human HRC serine 96, was mutated to alanine, using knock-in gene targeting...
September 1, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28859079/a-computational-model-of-spatio-temporal-cardiac-intracellular-calcium-handling-with-realistic-structure-and-spatial-flux-distribution-from-sarcoplasmic-reticulum-and-t-tubule-reconstructions
#3
Michael A Colman, Christian Pinali, Andrew W Trafford, Henggui Zhang, Ashraf Kitmitto
Intracellular calcium cycling is a vital component of cardiac excitation-contraction coupling. The key structures responsible for controlling calcium dynamics are the cell membrane (comprising the surface sarcolemma and transverse-tubules), the intracellular calcium store (the sarcoplasmic reticulum), and the co-localisation of these two structures to form dyads within which calcium-induced-calcium-release occurs. The organisation of these structures tightly controls intracellular calcium dynamics. In this study, we present a computational model of intracellular calcium cycling in three-dimensions (3-D), which incorporates high resolution reconstructions of these key regulatory structures, attained through imaging of tissue taken from the sheep left ventricle using serial block face scanning electron microscopy...
August 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28843346/beyond-the-critical-point-an-overview-of-excitotoxicity-calcium-overload-and-the-downstream-consequences
#4
REVIEW
Daniele Bano, Maria Ankarcrona
Over the past several decades, an overwhelming body of research has greatly expanded our understanding of the mechanisms underlying excitotoxicity in brain ischemia as well as in many chronic neurodegenerative diseases. The identification of an array of molecular targets has opened avenues for neuroprotective strategies and, consequently, has sparked considerable interest for their attractive therapeutic means as pharmacological options. The purpose of this work is to provide a general overview of neuronal excitotoxicity and the inevitable downstream consequences of Ca(2+) overload...
August 23, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28753475/presenilin-1-mutation-decreases-both-calcium-and-contractile-responses-in-cerebral-arteries
#5
Xavier Toussay, Jean-Luc Morel, Nathalie Biendon, Lolita Rotureau, François-Pierre Legeron, Marie-Charlotte Boutonnet, Yoon H Cho, Nathalie Macrez
Mutations or upregulation in presenilin 1 (PS1) gene are found in familial early-onset Alzheimer's disease or sporadic late-onset Alzheimer's disease, respectively. PS1 has been essentially studied in neurons and its mutation was shown to alter intracellular calcium (Ca(2+)) signals. Here, we showed that PS1 is expressed in smooth muscle cells (SMCs) of mouse cerebral arteries, and we assessed the effects of the deletion of exon 9 of PS1 (PS1dE9) on Ca(2+) signals and contractile responses of vascular SMC. Agonist-induced contraction of cerebral vessels was significantly decreased in PS1dE9 both in vivo and ex vivo...
June 24, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28739347/association-of-vitamin-d-receptor-gene-polymorphism-in-patients-with-type-2-diabetes-in-the-kashmir-valley
#6
Rawoof Malik, Rabia Farooq, Promela Mehta, Sheikh Ishaq, Insha Din, Parvaiz Shah, Sabhiya Majid
OBJECTIVES: Approx 1 billion people across various ethnic and age groups have vitamin D deficiency. The high prevalence of such a deficiency is an imperative public health issue because hypovitaminosis D is an autonomous risk factor for mortality in the general population. Beyond bone integrity and calcium homeostasis, it is involved in numerous physiologic and pathologic processes. The role of vitamin D in the pathogenesis and prevention of type 2 diabetes mellitus has sparked universal interest...
July 21, 2017: Canadian Journal of Diabetes
https://www.readbyqxmd.com/read/28731505/calcium-calmodulin-dependent-kinase-2-mediates-epac-induced-spontaneous-transient-outward-currents-in-rat-vascular-smooth-muscle
#7
Edward S A Humphries, Tomoko Kamishima, John M Quayle, Caroline Dart
KEY POINTS: The Ca(2+) and redox-sensing enzyme Ca(2+) /calmodulin-dependent kinase 2 (CaMKII) is a crucial and well-established signalling molecule in the heart and brain. In vascular smooth muscle, which controls blood flow by contracting and relaxing in response to complex Ca(2+) signals and oxidative stress, surprisingly little is known about the role of CaMKII. The vasodilator-induced second messenger cAMP can relax vascular smooth muscle via its effector, exchange protein directly activated by cAMP (Epac), by activating spontaneous transient outward currents (STOCs) that hyperpolarize the cell membrane and reduce voltage-dependent Ca(2+) influx...
September 15, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28701305/redox-and-activation-of-protein-kinase-a-dysregulates-calcium-homeostasis-in-pulmonary-vein-cardiomyocytes-of-chronic-kidney-disease
#8
Shih-Yu Huang, Yao-Chang Chen, Yu-Hsun Kao, Ming-Hsiung Hsieh, Yung-Kuo Lin, Shih-Ann Chen, Yi-Jen Chen
BACKGROUND: Chronic kidney disease (CKD) increases the occurrence of atrial fibrillation and pulmonary vein (PV) arrhythmogenesis. Calcium dysregulation and reactive oxygen species (ROS) enhance PV arrhythmogenic activity. The purposes of this study were to investigate whether CKD modulates PV electrical activity through dysregulation of calcium homeostasis and ROS. METHODS AND RESULTS: Biochemical and electrocardiographic studies were conducted in rabbits with and without CKD (induced by 150 mg/kg per day neomycin sulfate and 500 mg/kg per day cefazolin)...
July 12, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28674006/clusters-of-calcium-release-channels-harness-the-ising-phase-transition-to-confine-their-elementary-intracellular-signals
#9
Anna V Maltsev, Victor A Maltsev, Michael D Stern
Intracellular Ca signals represent a universal mechanism of cell function. Messages carried by Ca are local, rapid, and powerful enough to be delivered over the thermal noise. A higher signal-to-noise ratio is achieved by a cooperative action of Ca release channels such as IP3 receptors or ryanodine receptors arranged in clusters (release units) containing a few to several hundred release channels. The channels synchronize their openings via Ca-induced Ca release, generating high-amplitude local Ca signals known as puffs in neurons and sparks in muscle cells...
July 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28657075/bioinspired-onion-epithelium-like-structure-promotes-the-maturation-of-cardiomyocytes-derived-from-human-pluripotent-stem-cells
#10
Cong Xu, Li Wang, Yue Yu, Fangchao Yin, Xiaoqing Zhang, Lei Jiang, Jianhua Qin
Organized cardiomyocyte alignment is critical to maintain the mechanical properties of the heart. In this study, we present a new and simple strategy to fabricate a biomimetic microchip designed with an onion epithelium-like structure and investigate the guided behavior of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) on the substrate. The hiPSC-CMs were observed to be confined by the three dimensional surficial features morphologically, analogous to the in vivo microenvironment, and exhibited an organized anisotropic alignment on the onion epithelium-like structure with good beating function...
August 22, 2017: Biomaterials Science
https://www.readbyqxmd.com/read/28522367/qrs-t-wave-and-calcium-alternans-in-a-type-i-diabetic-mouse-model-for-spontaneous-postmyocardial-infarction-ventricular-tachycardia-a-mechanism-for-the-antiarrhythmic-effect-of-statins
#11
Hongwei Jin, Charles M Welzig, Mark Aronovitz, Farzad Noubary, Robert Blanton, Bo Wang, Mohammad Rajab, Alfred Albano, Mark S Link, Sami F Noujaim, Ho-Jin Park, Jonas B Galper
BACKGROUND: The incidence of sudden arrhythmic death is markedly increased in diabetics. OBJECTIVE: The purpose of this study was to develop a mouse model for postmyocardial infarction (post-MI) ventricular tachycardia (VT) in the diabetic heart and determine the mechanism of an antiarrhythmic effect of statins. METHODS: ECG transmitters were implanted in wild-type (WT), placebo, and pravastatin-treated type I diabetic Akita mice. MIs were induced by coronary ligation, and Ca(2+) transients were studied by optical mapping, and Ca(2+) transients and sparks in left ventricular myocytes (VM) by the Ionoptix system and confocal microscopy...
May 15, 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/28384221/kchip2-regulates-the-cardiac-ca2-transient-and-myocyte-contractility-by-targeting-ryanodine-receptor-activity
#12
Drew M Nassal, Xiaoping Wan, Haiyan Liu, Kenneth R Laurita, Isabelle Deschênes
Pathologic electrical remodeling and attenuated cardiac contractility are featured characteristics of heart failure. Coinciding with these remodeling events is a loss of the K+ channel interacting protein, KChIP2. While, KChIP2 enhances the expression and stability of the Kv4 family of potassium channels, leading to a more pronounced transient outward K+ current, Ito,f, the guinea pig myocardium is unique in that Kv4 expression is absent, while KChIP2 expression is preserved, suggesting alternative consequences to KChIP2 loss...
2017: PloS One
https://www.readbyqxmd.com/read/28332202/calcium-signalling-silencing-in-atrial-fibrillation
#13
Maura Greiser
Subcellular calcium signalling silencing is a novel and distinct cellular and molecular adaptive response to rapid cardiac activation. Calcium signalling silencing develops during short-term sustained rapid atrial activation as seen clinically during paroxysmal atrial fibrillation (AF). It is the first 'anti-arrhythmic' adaptive response in the setting of AF and appears to counteract the maladaptive changes that lead to intracellular Ca(2+) signalling instability and Ca(2+) -based arrhythmogenicity. Calcium signalling silencing results in a failed propagation of the [Ca(2+) ]i signal to the myocyte centre both in patients with AF and in a rabbit model...
June 15, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28329187/bumped-kinase-inhibitors-for-cryptosporidiosis-therapy
#14
Matthew A Hulverson, Sumiti Vinayak, Ryan Choi, Deborah A Schaefer, Alejandro Castellanos-Gonzalez, Rama S R Vidadala, Carrie F Brooks, Gillian T Herbert, Dana P Betzer, Grant R Whitman, Hayley N Sparks, Samuel L M Arnold, Kasey L Rivas, Lynn K Barrett, A Clinton White, Dustin J Maly, Michael W Riggs, Boris Striepen, Wesley C Van Voorhis, Kayode K Ojo
Bumped kinase inhibitors (BKIs) of Cryptosporidium parvum calcium-dependent protein kinase 1 (CpCDPK1) are leading candidates for treatment of cryptosporidiosis-associated diarrhea. Potential cardiotoxicity related to anti-human ether-à-go-go potassium channel (hERG) activity of the first-generation anti-Cryptosporidium BKIs triggered further testing for efficacy. A luminescence assay adapted for high-throughput screening was used to measure inhibitory activities of BKIs against C. parvum in vitro. Furthermore, neonatal and interferon γ knockout mouse models of C...
April 15, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28279675/synchronism-in-mitochondrial-ros-flashes-membrane-depolarization-and-calcium-sparks-in-human-carcinoma-cells
#15
Andrey V Kuznetsov, Sabzali Javadov, Valdur Saks, Raimund Margreiter, Michael Grimm
Mitochondria are major producers of reactive oxygen species (ROS) in many cells including cancer cells. However, complex interrelationships between mitochondrial ROS (mitoROS), mitochondrial membrane potential (ΔΨm) and Ca(2+) are not completely understood. Using human carcinoma cells, we further highlight biphasic ROS dynamics: - gradual mitoROS increase followed by mitoROS flash. Also, we demonstrate heterogeneity in rates of mitoROS generation and flash initiation time. Comparing mitochondrial and near-extra-mitochondrial signals, we show that mechanisms of mitoROS flashes in single mitochondria, linked to mitochondrial permeability transition pore opening (ΔΨm collapse) and calcium sparks, may involve flash triggering by certain levels of external ROS released from the same mitochondria...
June 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28209766/glycosylated-chromogranin-a-in-heart-failure-implications-for-processing-and-cardiomyocyte-calcium-homeostasis
#16
Anett Hellebø Ottesen, Cathrine R Carlson, William E Louch, Mai Britt Dahl, Ragnhild A Sandbu, Rune Forstrøm Johansen, Hilde Jarstadmarken, Magnar Bjørås, Arne Didrik Høiseth, Jon Brynildsen, Ivar Sjaastad, Mats Stridsberg, Torbjørn Omland, Geir Christensen, Helge Røsjø
BACKGROUND: Chromogranin A (CgA) levels have previously been found to predict mortality in heart failure (HF), but currently no information is available regarding CgA processing in HF and whether the CgA fragment catestatin (CST) may directly influence cardiomyocyte function. METHODS AND RESULTS: CgA processing was characterized in postinfarction HF mice and in patients with acute HF, and the functional role of CST was explored in experimental models. Myocardial biopsies from HF, but not sham-operated mice, demonstrated high molecular weight CgA bands...
February 2017: Circulation. Heart Failure
https://www.readbyqxmd.com/read/28169003/increased-calcium-leak-associated-with-reduced-calsequestrin-expression-in-hyperthyroid-cardiomyocytes
#17
David R de Alba-Aguayo, Natalia Pavón, Martha Mercado-Morales, Miyamin Miranda-Saturnino, Mavil López-Casamichana, Agustin Guerrero-Hernández, Angelica Rueda
INTRODUCTION: Calcium (Ca(2+)) leak during cardiac diastole is chiefly mediated by intracellular Ca(2+) channel/Ryanodine Receptors. Increased diastolic Ca(2+) leak has been proposed as the mechanism underlying the appearance of hereditary arrhythmias. However, little is known about alterations in diastolic Ca(2+) leak and the specific roles played by key intracellular Ca(2+)-handling proteins in hyperthyroidism, a known arrhythmogenic condition. AIM: We sought to determine whether there were modifications in diastolic Ca(2+) leak, based on the recording of Ca(2+) sparks and Ca(2+) waves; we also investigated changes in the expression and activity of key Ca(2+) handling proteins, including ryanodine receptors, Sarco-Endoplasmic Reticulum Ca(2+) ATPase pump and calsequestrin in isolated left-ventricular cardiomyocytes isolated from hyperthyroid rats...
January 23, 2017: Cell Calcium
https://www.readbyqxmd.com/read/27992670/dissection-of-the-effects-of-quercetin-on-mouse-myocardium
#18
Michel Santana Santos, Evaleide Diniz Oliveira, Artur Santos-Miranda, Jader Santos Cruz, Antônio Nei Santana Gondim, José Evaldo Rodrigues Menezes-Filho, Diego Santos Souza, Leidiane Pinho-da-Silva, Itamar Couto Guedes Jesus, Danilo Roman-Campos, Silvia Guatimosim, Aline Lara, Eduardo Antônio Conde-Garcia, Carla Maria Lins Vasconcelos
Quercetin is a plant flavonoid with several biological activities. This study aimed to describe quercetin effects on contractile and electrophysiological properties of the cardiac muscle as well as on calcium handling. Quercetin elicited positive inotropism that was significantly reduced by propranolol indicating an involvement of the sympathetic nervous system. In cardiomyocytes, 30 μM quercetin increased ICa,L at 0 mV from -0.95 ± 0.01 A/F to -1.21 ± 0.08 A/F. The membrane potential at which 50% of the channels are activated (V0...
June 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/27959915/numerical-approach-to-spatial-deterministic-stochastic-models-arising-in-cell-biology
#19
James C Schaff, Fei Gao, Ye Li, Igor L Novak, Boris M Slepchenko
Hybrid deterministic-stochastic methods provide an efficient alternative to a fully stochastic treatment of models which include components with disparate levels of stochasticity. However, general-purpose hybrid solvers for spatially resolved simulations of reaction-diffusion systems are not widely available. Here we describe fundamentals of a general-purpose spatial hybrid method. The method generates realizations of a spatially inhomogeneous hybrid system by appropriately integrating capabilities of a deterministic partial differential equation solver with a popular particle-based stochastic simulator, Smoldyn...
December 2016: PLoS Computational Biology
https://www.readbyqxmd.com/read/27882934/macrophage-dependent-il-1%C3%AE-production-induces-cardiac-arrhythmias-in-diabetic-mice
#20
Gustavo Monnerat, Micaela L Alarcón, Luiz R Vasconcellos, Camila Hochman-Mendez, Guilherme Brasil, Rosana A Bassani, Oscar Casis, Daniela Malan, Leonardo H Travassos, Marisa Sepúlveda, Juan Ignacio Burgos, Martin Vila-Petroff, Fabiano F Dutra, Marcelo T Bozza, Claudia N Paiva, Adriana Bastos Carvalho, Adriana Bonomo, Bernd K Fleischmann, Antonio Carlos Campos de Carvalho, Emiliano Medei
Diabetes mellitus (DM) encompasses a multitude of secondary disorders, including heart disease. One of the most frequent and potentially life threatening disorders of DM-induced heart disease is ventricular tachycardia (VT). Here we show that toll-like receptor 2 (TLR2) and NLRP3 inflammasome activation in cardiac macrophages mediate the production of IL-1β in DM mice. IL-1β causes prolongation of the action potential duration, induces a decrease in potassium current and an increase in calcium sparks in cardiomyocytes, which are changes that underlie arrhythmia propensity...
November 24, 2016: Nature Communications
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