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Calcium/calmodulin-dependent kinase type II

Adam S Helms, Francisco J Alvarado, Jaime Yob, Vi T Tang, Francis Pagani, Mark W Russell, Héctor H Valdivia, Sharlene M Day
BACKGROUND: -Aberrant calcium signaling may contribute to arrhythmias and adverse remodeling in hypertrophic cardiomyopathy (HCM). Mutations in sarcomere genes may distinctly alter calcium handling pathways. METHODS: -We analyzed gene expression, protein levels, and functional assays for calcium regulatory pathways in human HCM surgical samples with (n=25) and without (n=10) sarcomere mutations compared with control hearts (n=8). RESULTS: -Gene expression and protein levels for calsequestrin, L-type calcium channel, sodium-calcium exchanger, phospholamban (PLN), calcineurin, and calcium/calmodulin-dependent protein kinase type II (CaMKII) were similar in HCM compared to controls...
September 29, 2016: Circulation
Marisa Sepúlveda, Luis A Gonano, Manuel Viotti, Malena Morell, Paula Blanco, Micaela López Alarcón, Isalira Peroba Ramos, Adriana Bastos Carvalho, Emiliano Medei, Martín Vila Petroff
OBJECTIVES: Sepsis is associated with cardiac contractile dysfunction attributed to alterations in Ca handling. We examined the subcellular mechanisms involved in sarcoplasmic reticulum Ca loss that mediate altered Ca handling and contractile dysfunction associated with sepsis. DESIGN: Randomized controlled trial. SETTING: Research laboratory SUBJECTS:: Male wild type and transgenic mice INTERVENTIONS:: We induced sepsis in mice using the colon ascendens stent peritonitis model...
September 19, 2016: Critical Care Medicine
Elena Popugaeva, Ekaterina Pchitskaya, Ilya Bezprozvanny
Alzheimer's disease (AD) is the disease of lost memories. Synaptic loss is a major reason for memory defects in AD. Signaling pathways involved in memory loss in AD are under intense investigation. The role of deranged neuronal calcium (Ca(2+)) signaling in synaptic loss in AD is described in this review. Familial AD (FAD) mutations in presenilins are linked directly with synaptic Ca(2+) signaling abnormalities, most likely by affecting endoplasmic reticulum (ER) Ca(2+) leak function of presenilins. Excessive ER Ca(2+) release via type 2 ryanodine receptors (RyanR2) is observed in AD spines due to increase in expression and function of RyanR2...
September 15, 2016: Biochemical and Biophysical Research Communications
Dandan Wang, Yingguang Shan, Yan Huang, Yanhong Tang, Yuting Chen, Ran Li, Jing Yang, Congxin Huang
PURPOSE: Chronically elevated catecholamine levels activate cardiac β-adrenergic receptors, which play a vital role in the pathogenesis of heart failure. Evidence suggests that vasostatin-1 (VS-1) exerts anti-adrenergic effects on isolated and perfused hearts in vitro. Whether VS-1 ameliorates hypertrophy/remodeling by inducing the chronic activation of β-adrenergic receptors is unknown. The present study aims to test the efficacy of using VS-1 to treat the advanced hypertrophy/remodeling that result from chronic β-adrenergic receptor activation and to determine the cellular and molecular mechanisms that underlie this response...
October 2016: Cardiovascular Drugs and Therapy
Sen Zhu, Rakeshwar S Guleria, Candice M Thomas, Amanda Roth, F N U Gerilechaogetu, Rajesh Kumar, David E Dostal, Kenneth M Baker, Jing Pan
Retinoic acid receptor (RAR) has been implicated in pathological stimuli-induced cardiac remodeling. To determine whether the impairment of RARα signaling directly contributes to the development of heart dysfunction and the involved mechanisms, tamoxifen-induced myocardial specific RARα deletion (RARαKO) mice were utilized. Echocardiographic and cardiac catheterization studies showed significant diastolic dysfunction after 16 wks of gene deletion. However, no significant differences were observed in left ventricular ejection fraction (LVEF), between RARαKO and wild type (WT) control mice...
August 15, 2016: Journal of Molecular and Cellular Cardiology
Yuan-Long Li, Jun Zhou, Hai Zhang, Yi Luo, Li-Hong Long, Zhuang-Li Hu, Jian-Guo Chen, Fang Wang, Peng-Fei Wu
AIMS: Hydrogen sulfide (H2 S) has been widely accepted as a gas neuromodulator to regulate synaptic function. Herein, we set out to determine the effect of H2 S on α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) and its mechanism. METHODS: BS(3) protein cross-linking, Western blot, patch clamp, and biotin-switch assay. RESULTS: Bath application of H2 S donor NaHS (50 and 100 μM) rapidly promoted surface insertion of hippocampal AMPAR GluR1 subunit...
September 2016: CNS Neuroscience & Therapeutics
Laura T Haas, Stephen M Strittmatter
The dysfunction and loss of synapses in Alzheimer disease are central to dementia symptoms. We have recently demonstrated that pathological Amyloid β oligomer (Aβo) regulates the association between intracellular protein mediators and the synaptic receptor complex composed of cellular prion protein (PrP(C)) and metabotropic glutamate receptor 5 (mGluR5). Here we sought to determine whether Aβo alters the physiological signaling of the PrP(C)-mGluR5 complex upon glutamate activation. We provide evidence that acute exposure to Aβo as well as chronic expression of familial Alzheimer disease mutant transgenes in model mice prevents protein-protein interaction changes of the complex induced by the glutamate analog 3,5-dihydroxyphenylglycine...
August 12, 2016: Journal of Biological Chemistry
Hitoshi Uchinoumi, Yi Yang, Tetsuro Oda, Na Li, Katherina M Alsina, Jose L Puglisi, Ye Chen-Izu, Razvan L Cornea, Xander H T Wehrens, Donald M Bers
Diastolic calcium (Ca) leak via cardiac ryanodine receptors (RyR2) can cause arrhythmias and heart failure (HF). Ca/calmodulin (CaM)-dependent kinase II (CaMKII) is upregulated and more active in HF, promoting RyR2-mediated Ca leak by RyR2-Ser2814 phosphorylation. Here, we tested a mechanistic hypothesis that RyR2 phosphorylation by CaMKII increases Ca leak by promoting a pathological RyR2 conformation with reduced CaM affinity. Acute CaMKII activation in wild-type RyR2, and phosphomimetic RyR2-S2814D (vs. non-phosphorylatable RyR2-S2814A) knock-in mouse myocytes increased SR Ca leak, reduced CaM-RyR2 affinity, and caused a pathological shift in RyR2 conformation (detected via increased access of the RyR2 structural peptide DPc10)...
September 2016: Journal of Molecular and Cellular Cardiology
Fanny Toussaint, Chimène Charbel, Bruce G Allen, Jonathan Ledoux
First characterized in neuronal tissues, the multifunctional calcium/calmodulin-dependent protein kinase II (CaMKII) is a key signaling component in several mammalian biological systems. Its unique capacity to integrate various Ca(2+) signals into different specific outcomes is a precious asset to excitable and nonexcitable cells. Numerous studies have reported roles and mechanisms involving CaMKII in brain and heart tissues. However, corresponding functions in vascular cell types (endothelium and vascular smooth muscle cells) remained largely unexplored until recently...
September 1, 2016: American Journal of Physiology. Cell Physiology
David B Kurland, Volodymyr Gerzanich, Jason K Karimy, Seung Kyoon Woo, Rudi Vennekens, Marc Freichel, Bernd Nilius, Joseph Bryan, J Marc Simard
BACKGROUND: Harmful effects of activated microglia are due, in part, to the formation of peroxynitrite radicals, which is attributable to the upregulation of inducible nitric oxide (NO) synthase (NOS2). Because NOS2 expression is determined by Ca(2+)-sensitive calcineurin (CN) dephosphorylating nuclear factor of activated T cells (NFAT), and because Sur1-Trpm4 channels are crucial for regulating Ca(2+) influx, we hypothesized that, in activated microglia, Sur1-Trpm4 channels play a central role in regulating CN/NFAT and downstream target genes such as Nos2...
2016: Journal of Neuroinflammation
Lale Ozcan, Devram S Ghorpade, Ze Zheng, Jane Cristina de Souza, Ke Chen, Marc Bessler, Melissa Bagloo, Beth Schrope, Richard Pestell, Ira Tabas
Defective insulin signaling in hepatocytes is a key factor in type 2 diabetes. In obesity, activation of calcium/calmodulin-dependent protein kinase II (CaMKII) in hepatocytes suppresses ATF6, which triggers a PERK-ATF4-TRB3 pathway that disrupts insulin signaling. Elucidating how CaMKII suppresses ATF6 is therefore essential to understanding this insulin resistance pathway. We show that CaMKII phosphorylates and blocks nuclear translocation of histone deacetylase 4 (HDAC4). As a result, HDAC4-mediated SUMOylation of the corepressor DACH1 is decreased, which protects DACH1 from proteasomal degradation...
June 7, 2016: Cell Reports
Yan-Yang Wang, Shun Zhou, Ren Zhao, Ping Hai, Hong Zhe
CDDO-Me has exhibited a potent anticancer effect in human esophageal squamous cell carcinoma (ESCC) cells in our previous study, but the molecular interactome remains elusive. We applied the approach of stable-isotope labeling by amino acids in cell culture (SILAC) to assess the proteomic responses of CDDO-Me treatment in human ESCC Ec109 cells. The data were subsequently validated using Western blot assay. The results of our study revealed that CDDO-Me increased the expression level of 543 protein molecules, but decreased the expression level of 709 protein molecules in Ec109 cells...
2016: American Journal of Translational Research
Eef Dries, Demetrio J Santiago, Daniel M Johnson, Guillaume Gilbert, Patricia Holemans, Sanne M Korte, H Llewelyn Roderick, Karin R Sipido
In cardiac myocytes, β-adrenergic stimulation enhances Ca(2+) cycling through an integrated signalling cascade modulating L-type Ca(2+) channels (LTCC), phospholamban, and ryanodine receptors (RyRs). CaMKII and nitric oxide synthase1 (NOS1) are proposed as prime mediators for increasing RyR open probability. We investigate whether this pathway is confined to the high Ca(2+) microdomain of the dyadic cleft and thus to coupled RyRs. Pig ventricular myocytes are studied under whole-cell voltage-clamp and confocal line-scan imaging with Fluo-4 as a [Ca(2+) ]i indicator...
April 28, 2016: Journal of Physiology
Xufeng Chen, Jingjing Xing, Lei Jiang, Wenyi Qian, Yixin Wang, Hao Sun, Yu Wang, Hang Xiao, Jun Wang, Jinsong Zhang
Methamphetamine (METH), an illicit drug, is widely abused in many parts of the world. Mounting evidence shows that METH exposure contributes to neurotoxicity, particularly for the monoaminergic neurons. However, to date, only a few studies have tried to unravel the mechanisms involved in METH-induced non-monoaminergic neural damage. Therefore, in the present study, we tried to explore the mechanisms for METH-induced neural damage in cortical neurons. Our results showed that METH significantly increased intracellular [Ca(2) (+) ]i in Ca(2) (+) -containing solution rather than Ca(2) (+) -free solution...
November 2016: Journal of Applied Toxicology: JAT
Kui Ye, Qian-Qian Li, Xiao-Ju Jin, Li-Chao Peng
The aim of the present study was to investigate the effects of ketamine, imipramine, and ketamine plus imipramine on chronic depression-like behaviors of Wistar Kyoto (WKY) rats and underlying mechanism. Six-week-old Wistar rats were used as normal control. WKY rats, depression model animal, were injected intraperitoneally with ketamine (1 week, replaced with saline in 2(nd) week), imipramine (2 weeks), or ketamine in combination with imipramine. The depression-like behaviors were assessed by sucrose preference and forced swimming tests...
February 25, 2016: Sheng Li Xue Bao: [Acta Physiologica Sinica]
Marino DiFranco, Irina Kramerova, Julio L Vergara, Melissa Jan Spencer
BACKGROUND: Mutations in CAPN3 cause limb girdle muscular dystrophy type 2A (LGMD2A), a progressive muscle wasting disease. CAPN3 is a non-lysosomal, Ca-dependent, muscle-specific proteinase. Ablation of CAPN3 (calpain-3 knockout (C3KO) mice) leads to reduced ryanodine receptor (RyR1) expression and abnormal Ca2+/calmodulin-dependent protein kinase II (Ca-CaMKII)-mediated signaling. We previously reported that Ca(2+) release measured by fura2-FF imaging in response to single action potential stimulation was reduced in old C3KO mice; however, the use of field stimulation prevented investigation of the mechanisms underlying this impairment...
2016: Skeletal Muscle
Boxing Li, Michael R Tadross, Richard W Tsien
Voltage-gated CaV1.2 channels (L-type calcium channel α1C subunits) are critical mediators of transcription-dependent neural plasticity. Whether these channels signal via the influx of calcium ion (Ca(2+)), voltage-dependent conformational change (VΔC), or a combination of the two has thus far been equivocal. We fused CaV1.2 to a ligand-gated Ca(2+)-permeable channel, enabling independent control of localized Ca(2+) and VΔC signals. This revealed an unexpected dual requirement: Ca(2+) must first mobilize actin-bound Ca(2+)/calmodulin-dependent protein kinase II, freeing it for subsequent VΔC-mediated accumulation...
February 19, 2016: Science
Valerie T Ramírez, Eva Ramos-Fernández, Nibaldo C Inestrosa
Mastoparan-7 (Mas-7), an analogue of the peptide mastoparan, which is derived from wasp venom, is a direct activator of Pertussis toxin- (PTX-) sensitive G proteins. Mas-7 produces several biological effects in different cell types; however, little is known about how Mas-7 influences mature hippocampal neurons. We examined the specific role of Mas-7 in the development of dendritic spines, the sites of excitatory synaptic contact that are crucial for synaptic plasticity. We report here that exposure of hippocampal neurons to a low dose of Mas-7 increases dendritic spine density and spine head width in a time-dependent manner...
2016: Neural Plasticity
Rui Zhao, Shoubao Wang, Zhonglin Huang, Li Zhang, Xiuying Yang, Xiaoyu Bai, Dan Zhou, Zhizhen Qin, Guanhua Du
Serotonin transporter (SERT) is a critical determinant of synaptic serotonin (5-hydroxytryptamine, 5-HT) inactivation which plays a critical role in the pathology of depression and other mood disorders. Lipopolysaccharide (LPS), a potent activator of the inflammatory system, has been reported to cause depression symptoms by the modulation of SERT in vivo and in vitro. This study is aimed to investigate the underlying mechanism of LPS-induced SERT modulation. The 4-(4-(dimethylamino) styryl)-N-methylpyridinium iodide (ASP) assay was used to detect dynamic 5-HT uptake as read out of SERT activities in RBL-2H3 cells, and cytosol Ca(2+) concentrations ([Ca(2+)]i) and nitric oxide (NO) were examined...
December 2015: Bioscience Trends
Sun Woo Jin, Chul Yung Choi, Yong Pil Hwang, Hyung Gyun Kim, Se Jong Kim, Young Chul Chung, Kyung Jin Lee, Tae Cheon Jeong, Hye Gwang Jeong
Betulinic acid (BA) is a naturally occurring pentacyclic triterpene that attenuates vascular diseases and atherosclerosis, but the mechanism by which it stimulates endothelial nitric oxide synthase (eNOS) is unclear. eNOS is the key regulatory enzyme in the vascular endothelium. This study examined the intracellular pathways underlying the effects of BA on eNOS activity and endothelial nitric oxide (NO) production in endothelial cells. BA treatment induced both eNOS phosphorylation at Ser1177 and NO production...
February 3, 2016: Journal of Agricultural and Food Chemistry
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