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Qingsong Lin, Guiling Zhao, Xi Fang, Xiaohong Peng, Huayuan Tang, Hong Wang, Ran Jing, Jie Liu, W Jonathan Lederer, Ju Chen, Kunfu Ouyang
Inositol 1, 4, 5-trisphosphate receptor-mediated (IP3R-mediated) calcium (Ca(2+)) release has been proposed to play an important role in regulating vascular smooth muscle cell (VSMC) contraction for decades. However, whether and how IP3R regulates blood pressure in vivo remains unclear. To address these questions, we have generated a smooth muscle-specific IP3R triple-knockout (smTKO) mouse model using a tamoxifen-inducible system. In this study, the role of IP3R-mediated Ca(2+) release in adult VSMCs on aortic vascular contractility and blood pressure was assessed following tamoxifen induction...
October 20, 2016: JCI Insight
Silvia Honda Takada, Juliane Midori Ikebara, Erica de Sousa, Débora Sterzeck Cardoso, Rodrigo Ribeiro Resende, Henning Ulrich, Martin Rückl, Sten Rüdiger, Alexandre Hiroaki Kihara
It is well known that calcium (Ca(2+)) is involved in the triggering of neuronal death. Ca(2+) cytosolic levels are regulated by Ca(2+) release from internal stores located in organelles, such as the endoplasmic reticulum. Indeed, Ca(2+) transit from distinct cell compartments follows complex dynamics that are mediated by specific receptors, notably inositol trisphosphate receptors (IP3Rs). Ca(2+) release by IP3Rs plays essential roles in several neurological disorders; however, details of these processes are poorly understood...
October 22, 2016: Molecular Neurobiology
Xiuhong Cai, Xiang Li, Hong Qi, Fang Wei, Jianyong Chen, Jianwei Shuai
The gating properties of the inositol 1, 4, 5-trisphosphate (IP3) receptor (IP3R) are determined by the binding and unbinding capability of Ca(2+) ions and IP3 messengers. With the patch clamp experiments, the stationary properties have been discussed for Xenopus oocyte type-1 IP3R (Oo-IP3R1), type-3 IP3R (Oo-IP3R3) and Spodoptera frugiperda IP3R (Sf-IP3R). In this paper, in order to provide insights about the relation between the observed gating characteristics and the gating parameters in different IP3Rs, we apply the immune algorithm to fit the parameters of a modified DeYoung-Keizer model...
October 17, 2016: Physical Biology
Ching Man Chan, Jacqueline T M Aw, Sarah E Webb, Andrew L Miller
In zebrafish embryos, distinct Ca2+ transients are localized to the early cleavage furrows during the first few cell division cycles. These transients are generated mainly by release via IP3Rs in the endoplasmic reticulum, and they are necessary for furrow positioning, propagation, deepening and apposition. We previously showed, via the use of inhibitors, that store-operated Ca2+ entry (SOCE) also appears to be essential for maintaining the IP3R-mediated elevated levels of [Ca2+]i for the extended periods required for the completion of successful furrow deepening and daughter cell apposition in these large embryonic cells...
October 5, 2016: Zygote: the Biology of Gametes and Early Embryos
Laura Korvers, Amanda de Andrade Costa, Martin Mersch, Vitali Matyash, Helmut Kettenmann, Marcus Semtner
Microglia are the resident immune cells in the central nervous system and many of their physiological functions are known to be linked to intracellular calcium (Ca(2+)) signaling. Here we show that isolated and purified mouse microglia-either freshly or cultured-display spontaneous and transient Ca(2+) elevations lasting for around ten to twenty seconds and occurring at frequencies of around five to ten events per hour and cell. The events were absent after depletion of internal Ca(2+) stores, by phospholipase C (PLC) inhibition or blockade of inositol-1,4,5-trisphosphate receptors (IP3Rs), but not by removal of extracellular Ca(2+), indicating that Ca(2+) is released from endoplasmic reticulum intracellular stores...
September 22, 2016: Cell Calcium
Fei Liu, Zi-Fa Li, Zhen-Yong Wang, Lin Wang
Ca(2+) signaling plays a vital role in regulating apoptosis and autophagy. We previously proved that cytosolic Ca(2+) overload is involved in cadmium (Cd)-induced apoptosis in rat proximal tubular (rPT) cells, but the source of elevated cytosolic Ca(2+) concentration ([Ca(2+)]c) and the effect of potential subcellular Ca(2+) redistribution on apoptosis and autophagy remain to be elucidated. Firstly, data showed that Cd-induced elevation of [Ca(2+)]c was primarily generated intracellularly. Moreover, elevations of [Ca(2+)]c and mitochondrial Ca(2+) concentration ([Ca(2+)]mit) with depletion of endoplasmic reticulum (ER) Ca(2+) levels ([Ca(2+)]ER) were revealed in Cd-treated rPT cells, but this subcellular Ca(2+) redistribution was significantly suppressed by 2-Aminoethoxydiphenyl borate (2-APB)...
September 14, 2016: Journal of Inorganic Biochemistry
Clark A Briggs, Shreaya Chakroborty, Grace E Stutzmann
The current state of the AD research field is highly dynamic is some respects, while seemingly stagnant in others. Regarding the former, our current lack of understanding of initiating disease mechanisms, the absence of effective treatment options, and the looming escalation of AD patients is energizing new research directions including a much-needed re-focusing on early pathogenic mechanisms, validating novel targets, and investigating relevant biomarkers, among other exciting new efforts to curb disease progression and foremost, preserve memory function...
September 20, 2016: Biochemical and Biophysical Research Communications
Mi-Hee Lim, In Cheul Jeung, Jinyoung Jeong, Sung-Jin Yoon, Sang-Hyun Lee, Jongjin Park, Yu-Seon Kang, Hansu Lee, Young-Jun Park, Hee Gu Lee, Seon-Jin Lee, Baek Soo Han, Nam Woong Song, Sang Chul Lee, Jang-Seong Kim, Kwang-Hee Bae, Jeong-Ki Min
Despite the rapid expansion of the biomedical applications of graphene oxide (GO), safety issues related to GO, particularly with regard to its effects on vascular endothelial cells (ECs), have been poorly evaluated. To explore possible GO-mediated vasculature cytotoxicity and determine lateral GO size relevance, we constructed four types of GO: micrometer-sized GO (MGO; 1089.9 ± 135.3 nm), submicrometer-sized GO (SGO; 390.2 ± 51.4 nm), nanometer-sized GO (NGO; 65.5 ± 16.3 nm), and graphene quantum dots (GQDs)...
September 15, 2016: Acta Biomaterialia
Ritesh K Srivastava, Changzhao Li, Aftab Ahmad, Onika Abrams, Marina S Gorbatyuk, Kevin S Harrod, Ronald C Wek, Farrukh Afaq, Mohammad Athar
Arsenic is a mitochondrial toxin, and its derivatives, such as arsenic trioxide (ATO), can trigger endoplasmic reticulum (ER) and the associated unfolded protein response (UPR). Here, we show that arsenic induction of the UPR triggers ATF4, which is involved in regulating this ER-mitochondrial crosstalk that is important for the molecular pathogenesis of arsenic toxicity. Employing ATF4(+/+) and ATF4(-/-) MEFs, we show that ATO induces UPR and impairs mitochondrial integrity in ATF4(+/+) MEF cells which is largely ablated upon loss of ATF4...
November 1, 2016: Archives of Biochemistry and Biophysics
Yuan Liu, Xue-Chun Wang, Dan Hu, Shu-Ran Huang, Qing-Shu Li, Zhi Li, Yan Qu
Heat shock protein 70 (HSP70) maintains Ca(2+) homeostasis in PC12 cells, which may protect against apoptosis; however, the mechanisms of neuroprotection are unclear. Therefore, in this study, we examined Ca(2+) levels in PC12 cells transfected with an exogenous lentiviral HSP70 gene expression construct, and we subsequently subjected the cells to ischemia-hypoxia/reoxygenation injury. HSP70 overexpression increased neuronal viability and ATPase activity, and it decreased cellular reactive oxygen species levels and intracellular Ca(2+) concentration after hypoxia/reoxygenation...
July 2016: Neural Regeneration Research
Sumita Chakraborty, Bipan K Deb, Tetyana Chorna, Vera Konieczny, Colin W Taylor, Gaiti Hasan
Store-operated Ca(2+) entry (SOCE) occurs when loss of Ca(2+) from the endoplasmic reticulum (ER) stimulates the Ca(2+) sensor, STIM, to cluster and activate the plasma membrane Ca(2+) channel Orai (encoded by Olf186-F in flies). Inositol 1,4,5-trisphosphate receptors (IP3Rs, which are encoded by a single gene in flies) are assumed to regulate SOCE solely by mediating ER Ca(2+) release. We show that in Drosophila neurons, mutant IP3R attenuates SOCE evoked by depleting Ca(2+) stores with thapsigargin. In normal neurons, store depletion caused STIM and the IP3R to accumulate near the plasma membrane, association of STIM with Orai, clustering of STIM and Orai at ER-plasma-membrane junctions and activation of SOCE...
October 15, 2016: Journal of Cell Science
Brendan A Bicknell, Geoffrey J Goodhill
Many ion channels exhibit a slow stochastic switching between distinct modes of gating activity. This feature of channel behavior has pronounced implications for the dynamics of ionic currents and the signaling pathways that they regulate. A canonical example is the inositol 1,4,5-trisphosphate receptor (IP3R) channel, whose regulation of intracellular Ca(2+) concentration is essential for numerous cellular processes. However, the underlying biophysical mechanisms that give rise to modal gating in this and most other channels remain unknown...
September 6, 2016: Proceedings of the National Academy of Sciences of the United States of America
Khushboo Singh, James M Briggs
Mutations in the translocated BCL2 gene are often detected in diffuse large B-cell lymphomas (DLBCLs), indicating both their significance and pervasiveness. Large series genome sequencing of more than 200 DLBCLs has identified frequent BCL2 mutations clustered in the exons coding for the BH4 domain and the folded loop domain (FLD) of the protein. However, BCL2 mutations are mostly contemplated to represent bystander events with negligible functional impact on the pathogenesis of DLBCL. BCL2 arbitrates apoptosis through a classic interaction between its hydrophobic groove forming BH1-3 domains and the BH3 domain of pro-apoptotic members of the BCL2 family...
July 2016: Mutation Research. Reviews in Mutation Research
Sona Hudecova, Jana Markova, Veronika Simko, Lucia Csaderova, Tibor Stracina, Marta Sirova, Michaela Fojtu, Eliska Svastova, Paulina Gronesova, Michal Pastorek, Marie Novakova, Dana Cholujova, Juraj Kopacek, Silvia Pastorekova, Jan Sedlak, Olga Krizanova
In this study we show that anti-tumor effect of sulforaphane (SFN) is partially realized through the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1). This effect was verified in vitro on three different stable cell lines and also in vivo on the model of nude mice with developed tumors. Early response (6 hours) of A2780 ovarian carcinoma cells to SFN treatment involves generation of mitochondrial ROS and increased transcription of NRF2 and its downstream regulated genes including heme oxygenase 1, NAD(P)H:quinine oxidoreductase 1, and KLF9...
April 25, 2016: Oncotarget
Catherine A Rivet, Ariel S Kniss-James, Margaret A Gran, Anish Potnis, Abby Hill, Hang Lu, Melissa L Kemp
T cells reach a state of replicative senescence characterized by a decreased ability to proliferate and respond to foreign antigens. Calcium release associated with TCR engagement is widely used as a surrogate measure of T cell response. Using an ex vivo culture model that partially replicates features of organismal aging, we observe that while the amplitude of Ca2+ signaling does not change with time in culture, older T cells exhibit faster Ca2+ rise and a faster decay. Gene expression analysis of Ca2+ channels and pumps expressed in T cells by RT-qPCR identified overexpression of the plasma membrane CRAC channel subunit ORAI1 and PMCA in older T cells...
2016: PloS One
Shu-Chung Hsieh, Chun-Chi Wu, Shih-Lan Hsu, Jung-Hsing Yen
AIMS: To explore the effect and molecular mechanism of gallic acid (GA) on the cytostatic and cytotoxicity of hypertrophic scar fibroblasts (HSFs). MATERIALS AND METHODS: HSFs were treated with a serial dose of GA for indicated time. The cytostatic and cytotoxicity of GA were evaluated by microscopy, trypan blue exclusion assay and LDH releasing. The mechanisms of GA-induced cytostatic were examined by cell cycle distribution assay and the expression of cell cycle-relative protein...
August 8, 2016: Life Sciences
Keiko Uchida, Maki Nakazawa, Chihiro Yamagishi, Katsuhiko Mikoshiba, Hiroyuki Yamagishi
The embryonic-maternal interface of the placental labyrinth, allantois, and yolk sac are vital during embryogenesis; however, the precise mechanism underlying the vascularization of these structures remains unknown. Herein we focus on the role of inositol 1,4,5-trisphosphate (IP3) receptors (IP3R), which are intracellular Ca(2+) release channels, in placentation. Double knockout (DKO) of type 1 and 3 IP3Rs (IP3R1 and IP3R3, respectively) in mice resulted in embryonic lethality around embryonic day (E) 11.5...
October 1, 2016: Developmental Biology
X Song, Y Zhang, H Wang, H Wen, C Zhao, Y Lan, L Pan, C Zhang, M Cheng
The objective of this study is to investigate whether the inhibition of tradinterol (SPFF) against acetylcholine (ACh)-induced proliferation is mediated by Ca(2+) signaling in airway smooth muscle cells (ASMCs), and whether stereoselectivity of the drug exists. Guinea pig ASMCs were primarily prepared with the method described and treated with ACh combined to SPFF isomers for 24 or 48 hours, respectively. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was used to determine the proliferation of the guinea pig ASMCs...
June 2016: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
Lea K Seidlmayer, Johannes Kuhn, Annette Berbner, Paula-Anahi Arias-Loza, Tatjana Williams, Mathias Kaspar, Martin Czolbe, Jennifer Q Kwong, Jeffery D Molkentin, Katrin Gertrud Heinze, Elena N Dedkova, Oliver Ritter
AIMS: Elevated levels of inositol 1,4,5-trisphosphate (IP3) in adult cardiac myocytes are typically associated with the development of cardiac hypertrophy, arrhythmias, and heart failure. IP3 enhances intracellular Ca(2+ )release via IP3 receptors (IP3Rs) located at the sarcoplasmic reticulum (SR). We aimed to determine whether IP3-induced Ca(2+ )release affects mitochondrial function and determine the underlying mechanisms. METHODS AND RESULTS: We compared the effects of IP3Rs- and ryanodine receptors (RyRs)-mediated cytosolic Ca(2+ )elevation achieved by endothelin-1 (ET-1) and isoproterenol (ISO) stimulation, respectively, on mitochondrial Ca(2+ )uptake and adenosine triphosphate (ATP) generation...
October 2016: Cardiovascular Research
Hristina Ivanova, Abigael Ritane, Larry Wagner, Tomas Luyten, George Shapovalov, Kirsten Welkenhuyzen, Bruno Seitaj, Giovanni Monaco, Humbert De Smedt, Natalia Prevarskaya, David I Yule, Jan B Parys, Geert Bultynck
The anti-apoptotic Bcl-2 protein is emerging as an efficient inhibitor of IP3R function, contributing to its oncogenic properties. Yet, the underlying molecular mechanisms remain not fully understood. Using mutations or pharmacological inhibition to antagonize Bcl-2's hydrophobic cleft, we excluded this functional domain as responsible for Bcl-2-mediated IP3Rs inhibition. In contrast, the deletion of the C-terminus, containing the trans-membrane domain, which is only present in Bcl-2α, but not in Bcl-2β, led to impaired inhibition of IP3R-mediated Ca2+ release and staurosporine-induced apoptosis...
August 2, 2016: Oncotarget
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