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Wei Lei, Jianan Ni, Xueting Xia, Min Jiang, Gang Bai
Coronary heart disease is a vital cause of morbidity and mortality worldwide, and calcium channel blockers (CCBs) are important drugs that can be used to treat cardiovascular diseases. Suxiao Jiuxin Pill (SX), a traditional Chinese medicine, is widely used as an emergency drug for coronary heart disease therapy. However, understanding its potential mechanism in intracellular calcium concentration ([Ca2+ ]i ) modulation remains a challenge. To identify the active pharmacological ingredients (APIs) and reveal a novel combination therapy for ameliorating cardiovascular diseases, the ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) combined with a dual-luciferase reporter [Ca2+ ]i assay system was applied...
June 8, 2018: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Augusto C Montezano, Livia De Lucca Camargo, Patrik Persson, Francisco J Rios, Adam P Harvey, Aikaterini Anagnostopoulou, Roberto Palacios, Ana Caroline P Gandara, Rheure Alves-Lopes, Karla B Neves, Maria Dulak-Lis, Chet E Holterman, Pedro Lagerblad de Oliveira, Delyth Graham, Christopher Kennedy, Rhian M Touyz
BACKGROUND: NADPH Oxidase 5 (Nox5) is a calcium-sensitive superoxide-generating Nox. It is present in lower forms and higher mammals, but not in rodents. Nox5 is expressed in vascular cells, but the functional significance remains elusive. Given that contraction is controlled by calcium and reactive oxygen species, both associated with Nox5, we questioned the role of Nox5 in pro-contractile signaling and vascular function. METHODS AND RESULTS: Transgenic mice expressing human Nox5 in a vascular smooth muscle cell-specific manner (Nox5 mice) and Rhodnius prolixus , an arthropod model that expresses Nox5 endogenoulsy, were studied...
June 15, 2018: Journal of the American Heart Association
Le Gui, Xin Guo, Zhe Zhang, Hui Xu, Ya-Wei Ji, Ren-Jun Wang, Jiang-Hua Zhu, Qing-Hui Chen
Activation of the Ca2+ /calmodulin-dependent protein kinase II isoform δA (CaMKIIδA) disturbs intracellular Ca2+ homeostasis in cardiomyocytes during chronic heart failure (CHF). We hypothesized that upregulation of CaMKIIδA in cardiomyocytes might enhance Ca2+ leak from the sarcoplasmic reticulum (SR) via activation of phosphorylated ryanodine receptor type 2 (P-RyR2) and decrease Ca2+ uptake by inhibition of SR calcium ATPase 2a (SERCA2a). In this study, CHF was induced in rats by ligation of the left anterior descending coronary artery...
June 14, 2018: Acta Pharmacologica Sinica
Colline Sanchez, Christine Berthier, Bruno Allard, Jimmy Perrot, Clément Bouvard, Hidekazu Tsutsui, Yasushi Okamura, Vincent Jacquemond
Ion channel activity in the plasma membrane of living cells generates voltage changes that are critical for numerous biological functions. The membrane of the endoplasmic/sarcoplasmic reticulum (ER/SR) is also endowed with ion channels, but whether changes in its voltage occur during cellular activity has remained ambiguous. This issue is critical for cell functions that depend on a Ca2+ flux across the reticulum membrane. This is the case for contraction of striated muscle, which is triggered by opening of ryanodine receptor Ca2+ release channels in the SR membrane in response to depolarization of the transverse invaginations of the plasma membrane (the t-tubules)...
June 13, 2018: Journal of General Physiology
Daniel B Yaeger, Emma J Coddington
Neurons in the medullary reticular formation are involved in the control of postural and locomotor behaviors in all vertebrates. Reticulospinal neurons in this brain region provide one of the major descending projections to the spinal cord. Although neurons in the newt medullary reticular formation have been extensively studied using in vivo extracellular recordings, little is known of their intrinsic biophysical properties or of the underlying circuitry of this region. Using whole-cell patch-clamp recordings in brain slices containing the rostromedial reticular formation (rmRF) from adult male newts, we observed spontaneous miniature outward currents (SMOCs) in approximately two-thirds of neurons...
June 13, 2018: Journal of Neurophysiology
Jin-Da Wang, Li-Fei Chen, Ya-Ru Wang, Hua-Ying Fu, Ahmad Ali, Da Xiao, Ran Wang, San-Ji Gao
The ryanodine receptors of insects are the main target sites of diamide insecticides, which show highly selective insecticidal activity relative to toxicity in mammals and provide a novel option for managing lepidopteran pests. The oriental armyworm, Mythimna separata (Walker), is a destructive pest of agricultural crops, and great efforts have been undertaken to control this pest including repeated insecticide applications. In this study, full-length cDNA of a ryanodine receptor gene from M. separata (MsRyR) was cloned and characterized...
June 2018: Pesticide Biochemistry and Physiology
Williams Ernesto Miranda, Van A Ngo, Ruiwu Wang, Lin Zhang, S R Wayne Chen, Sergei Yu Noskov
Membrane proteins known as Ryanodine Receptors (RyRs) display large-conductance of ~1 nS and nearly-ideal charge selectivity. Both properties are inversely correlated in other large-conductance but non-selective biological nanopores (i.e. alpha-hemolysin) used as industrial biosensors. Although recent Cryo-EM structures of RyR2 show similarities to K+ and Na+-selective channels, it remains unclear whether the similar ion conduction mechanisms occur in RyR2. Here, we combine micro-seconds of all-atom molecular dynamics (MD) simulations with mutagenesis and electrophysiology experiments to investigate large K+ conductance and charge (cation-vs-anion) selectivity in an open-state structure of RyR2...
June 10, 2018: Journal of Physical Chemistry Letters
Matthew S Delfiner, Colleen Nofi, Ying Li, A Martin Gerdes, Youhua Zhang
BACKGROUND: Both vagal (VS) and sympathetic (SS) stimulations can increase atrial fibrillation (AF) inducibility, with VS being known as more arrhythmogenic in normal hearts. Heart failure (HF) results in autonomic dysfunction (characterized by sympathetic activation and vagal withdrawal) and is associated with an increased AF incidence. This study investigated whether failing hearts, compared to normal-controls, respond differently to autonomic stimulation induced AF arrhythmogenesis and the effect of dantrolene on SS enhanced AF in HF...
June 6, 2018: Journal of Cardiac Failure
Tatiana M Vinogradova, Syevda Sirenko, Yevgeniya O Lukyanenko, Dongmei Yang, Kirill V Tarasov, Alexey E Lyashkov, Nevin J Varghese, Yue Li, Khalid Chakir, Bruce Ziman, Edward G Lakatta
BACKGROUND: Spontaneous firing of sinoatrial node cells (SANCs) is regulated by cAMP-mediated, PKA (protein kinase A)-dependent (cAMP/PKA) local subsarcolemmal Ca2+ releases (LCRs) from RyRs (ryanodine receptors). LCRs occur during diastolic depolarization and activate an inward Na+ /Ca2+ exchange current that accelerates diastolic depolarization rate prompting the next action potential. PDEs (phosphodiesterases) regulate cAMP-mediated signaling; PDE3/PDE4 represent major PDE activities in SANC, but how they modulate LCRs and basal spontaneous SANC firing remains unknown...
June 2018: Circulation. Arrhythmia and Electrophysiology
Helmut Plattner, Alexei Verkhratsky
The aim of the present article is to analyse the evolutionary links between protozoa and neuronal and neurosecretory cells. To this effect we employ functional and topological data available for ciliates, in particular for Paramecium. Of note, much less data are available for choanoflagellates, the progenitors of metazoans, which currently are in the focus of metazoan genomic data mining. Key molecular players are found from the base to the highest levels of eukaryote evolution, including neurones and neurosecretory cells...
July 2018: Cell Calcium
Tao Li, Lingyun Wang, Teng Ma, Shouyu Wang, Jianqin Niu, Hongli Li, Lan Xiao
Increased intracellular Ca2+ in oligodendrocyte progenitor cells (OPCs) is important to initiate their differentiation, but the intracellular Ca2+ channel involved in this process remains unclear. As a Ca2+ -induced Ca2+ release (CICR) channel that mediates endoplasmic reticulum (ER) Ca2+ release, the role of ryanodine receptors (RyRs) in oligodendroglial development is unexplored. In the present study, we observed that among the three mammalian isoforms, oligodendroglial lineage cells selectively expressed RyR3...
2018: Frontiers in Molecular Neuroscience
Jing-Bo Liu, Feng-Yun Li, Jing-Yue Dong, Yu-Xin Li, Xiu-Lan Zhang, Yuan-Hong Wang, Li-Xia Xiong, Zheng-Ming Li
A series of novel anthranilic diamides derivatives (7a-s) containing halogen, trifluoromethyl group and cyano group were designed, synthesized, and characterized by melting point, 1 H NMR, 13 C NMR and elemental analyses. The bioactivity revealed that most of them showed moderate to excellent activities against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella). Above all, the larvicidal activity of 7o against oriental armyworm was 100% and 40% at 0.25 and 0.1 mg L-1 , comparable to that of the standard chlorantraniliprole (100%, 0...
May 19, 2018: Bioorganic & Medicinal Chemistry
Maria J Crespo, Marie Roman, Jonathan Matias, Myrna Morales, Hector Torres, Jose Quidgley
Diabetics have a higher risk of developing cerebral vasospasms (CVSP) than nondiabetics. The addition of the ryanodine receptor (RyR) blocker dantrolene to standard therapies reduces vasospasms in nondiabetics. Whether diabetics with CVSP also benefit from this drug, however, is unknown. We evaluated the effects of a 30 min incubation with dantrolene (50  μ M), nimodipine (50 nM), and both drugs in combination, on phenylephrine- (PHE-) induced contraction and on acetylcholine- (ACh-) induced relaxation in aortic rings from streptozotocin (STZ) diabetic rats...
2018: International Journal of Endocrinology
Ian Warbrick, Simon W Rabkin
Heart failure with preserved ejection fraction (HFpEF) represents an important cardiac condition because of its increasing prevalence, resistance to treatment and high associated morbidity and mortality. Two of the major mechanisms responsible for HFpEF are impaired cardiomyocyte sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a) transports calcium reuptake into the SR and cardiac fibroblasts/myofibroblasts that produce collagen or myocardial fibrosis. Phospholamban (PLB), in the SR and endoplasmic reticulum, is the primary regulator of SERCA2a in the heart and acts as a reversible inhibitor of SERCA2a...
May 25, 2018: Peptides
Nabil El Khoury, Jenna Ross, Valérie Long, Simon Thibault, Nathalie Ethier, Céline Fiset
Aims: During pregnancy, there is a significant increase in heart rate (HR) potentially associated with an increased risk of arrhythmias or exacerbation of pre-existing cardiac conditions endangering both mother and fetus. Calcium homeostasis plays an important role in regulating automaticity of the sinoatrial node (SAN) however, its contribution to the accelerated HR during pregnancy remains unknown. Methods and Results: Using murine SAN cells, we showed that pregnancy increased L-type Ca2+ current (ICaL) and CaV1...
May 23, 2018: Cardiovascular Research
Bartlomiej J Troczka, Ewan Richardson, Rafael Homem, T G Emyr Davies
Using publicly available genomic data, combined with RT-PCR validation, we explore structural genomic variation for two major ion channels across insect classes. We have manually curated Ryanodine receptor (RyR) and inositol 1,4,5-trisphosphate receptor (IP3 R) ORFs and their corresponding genomic structures from 26 different insects covering major insect orders. We found that, despite high protein identity for both RyRs (>75%) and IP3 Rs (~67%), the overall complexity of the gene structure varies greatly between different insect orders with the simplest genes (fewest introns) found in Diptera and the most complex in Lepidoptera...
May 21, 2018: Gene
Peter Nanasi, Istvan Komaromi, Janos Almassy
Clinical treatment of heart failure is still not fully solved. A novel class of agents, the myosin motor activators, acts directly on cardiac myosin resulting in an increased force generation and prolongation of contraction. Omecamtiv mecarbil, the lead molecule of this group, is now in human 3 phase displaying promising clinical performance. However, omecamtiv mecarbil is not selective to myosin, since it readily binds to and activates cardiac ryanodine receptors (RyR-2), an effect that may cause complications is case of overdose...
May 24, 2018: Canadian Journal of Physiology and Pharmacology
Lowell Davis, James Musso, Divya Soman, Samantha Louey, Jonathan William Nelson, Sonnet S Jonker
Fetal anemia causes rapid and profound changes in cardiac structure and function, stimulating proliferation of the cardiac myocytes, expansion of the coronary vascular tree, and impairing early contraction and relaxation. While HIF-1α is sure to play a role, adenosine, a metabolic byproduct that increases coronary flow and growth, is implicated as a major stimulus for these adaptations. We hypothesized that genes involved in myocardial adenosine signaling would be up-regulated in chronically anemic fetuses, and that calcium handling genes would be down-regulated...
May 23, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Mauricio Henriquez, Marcelo Fonseca, Jose F Perez-Zoghbi
KEY POINTS: We investigated the excitation-contraction coupling mechanisms in small pulmonary veins (SPVs) in rat precision-cut lung slices. We found that SPVs contract strongly and reversibly in response to extracellular ATP and other vasoconstrictors, including angiotensin-II and endothelin-1. ATP-induced vasoconstriction in SPVs was associated with the stimulation of purinergic P2Y2 receptors in vascular smooth muscle cell, activation of phospholipase C-β and the generation of intracellular Ca2+ oscillations mediated by cyclic Ca2+ release events via the inositol 1,4,5-trisphosphate receptor...
May 23, 2018: Journal of Physiology
Stephen Zachary, Nathaniel Nowak, Pankhuri Vyas, Luke Bonanni, Paul Albert Fuchs
Until postnatal day 12, inner hair cells of the rat cochlea are invested with both afferent and efferent synaptic connections. With the onset of hearing at P12, the efferent synapses disappear, and afferent (ribbon) synapses operate with greater efficiency. This change coincides with increased expression of voltage-gated potassium channels, the loss of calcium-dependent electrogenesis, and the onset of graded receptor potentials driven by sound. The transient efferent synapses include near-membrane postsynaptic cisterns thought to regulate calcium influx through the hair cell's α9α10-nAChR that activates small conductance Ca2+ -activated K+ (SK) channels...
May 22, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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