Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells

Frontiers in Cellular Neuroscience, Journal Year: 2020, Volume and Issue: 14

Published: March 19, 2020

A plethora of neurological disorders shares a final common deadly pathway known as excitotoxicity. Among these disorders, ischemic injury is prominent cause death and disability worldwide. Brain ischemia stems from cardiac arrest or stroke, both responsible for insufficient blood supply to the brain parenchyma. Glucose oxygen deficiency disrupts oxidative phosphorylation, which results in energy depletion ionic imbalance, followed by cell membrane depolarization, calcium (Ca2+) overload, extracellular accumulation excitatory amino acid glutamate. If tight physiological regulation fails clear surplus this neurotransmitter, subsequent prolonged activation glutamate receptors forms vicious circle between elevated concentrations intracellular Ca2+ ions aberrant release, aggravating effect pathway. The downstream Ca2+-dependent enzymes has catastrophic impact on nervous tissue leading death, accompanied formation free radicals, edema, inflammation. After decades "neuron-centric" approaches, recent research also finally shed some light role glial cells diseases. It becoming more evident that neurons glia depend each other. Neuronal cells, astrocytes, microglia, NG2 glia, oligodendrocytes all have their roles what However, who main contributor pathway, unsuspecting victim? In review article, we summarize so-far-revealed central system, with particular attention ischemia-induced excitotoxicity, its origins, consequences.

Language: Английский

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Physiological role of taurine – from organism to organelle

Acta Physiologica, Journal Year: 2014, Volume and Issue: 213(1), P. 191 - 212

Published: Aug. 20, 2014

Taurine is often referred to as a semi-essential amino acid newborn mammals have limited ability synthesize taurine and rely on dietary supply. not thought be incorporated into proteins no aminoacyl tRNA synthetase has yet been identified oxidized in mammalian cells. However, contributes significantly the cellular pool of organic osmolytes accordingly acknowledged for its role cell volume restoration following osmotic perturbation. This review describes homeostasis cells organelles with emphasis biophysics/membrane dynamics, regulation transport involved active uptake passive release well physiological processes, example, development, lung function, mitochondrial antioxidative defence apoptosis which seem affected by shift expression transporters and/or content.

Language: Английский

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Monitoring tropical forest degradation using spectral unmixing and Landsat time series analysis

Remote Sensing of Environment, Journal Year: 2018, Volume and Issue: 238, P. 110968 - 110968

Published: Nov. 28, 2018

Language: Английский

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Subunit composition of VRAC channels determines substrate specificity and cellular resistance to P t‐based anti‐cancer drugs

The EMBO Journal, Journal Year: 2015, Volume and Issue: 34(24), P. 2993 - 3008

Published: Nov. 3, 2015

Article3 November 2015Open Access Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs Rosa Planells-Cases Leibniz-Institut für Molekulare Pharmakologie (FMP), Max-Delbrück-Centrum Medizin (MDC), Berlin, Germany Search for more papers by this author Darius Lutter Charlotte Guyader Division Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, Nora M Gerhards Institute Animal Pathology, Vetsuisse Faculty, University Bern, Switzerland Florian Ullrich Deborah A Elger Asli Kucukosmanoglu Guotai Xu Felizia K Voss S Momsen Reincke Tobias Stauber Vincent Blomen Biochemistry, Daniel J Vis Carcinogenesis, Lodewyk F Wessels Thijn R Brummelkamp Piet Borst Sven Rottenberg Corresponding Author Thomas Jentsch NeuroCure Cluster Excellence, Charité Universitätsmedizin, Information Planells-Cases1, Lutter1, Guyader2, Gerhards3, Ullrich1, Elger1, Kucukosmanoglu4, Xu4, Voss1, Reincke1, Stauber1,8, Blomen5, Vis6, Wessels6, Brummelkamp5, Borst2, 3,4 1,7 1Leibniz-Institut 2Division 3Institute 4Division 5Division 6Division 7NeuroCure 8Present address: Chemistry Freie Universitaet Berlin *Corresponding author. Tel: +41 31 6312395; E-mail: [email protected] +49 30 94062961; EMBO Journal (2015)34:2993-3008https://doi.org/10.15252/embj.201592409 See also: T Voets et al (December 2015) PDFDownload PDF article text main figures. Peer ReviewDownload a summary the editorial decision process including letters, reviewer comments responses feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Although platinum-based are widely used chemotherapeutics cancer treatment, determinants tumor cell responsiveness remain poorly understood. We show that loss subunits LRRC8A LRRC8D heteromeric LRRC8 volume-regulated anion (VRACs) increased clinically relevant cisplatin/carboplatin concentrations. Under isotonic conditions, about 50% cisplatin uptake depended on LRRC8D, but neither LRRC8C nor LRRC8E. Cell swelling strongly enhanced LRRC8-dependent uptake, bolstering notion enters cells through VRAC. disruption also suppressed drug-induced apoptosis independently from drug possibly impairing VRAC-dependent apoptotic volume decrease. Hence, mediating facilitating apoptosis, plays dual role in response. Incorporation subunit into substantially its permeability osmolyte taurine, indicating proteins form channel pore. Our work suggests LRRC8D-containing VRACs crucial regulation an important organic may influence tumors. Synopsis were recently shown constitute elusive This study shows regulate both drugs, thus modulating tumour responses. Substrate selectivity depends composition, suggesting these mediates carboplatin. By In addition enabling transport, facilitates taurine. Introduction platinum-containing cisplatin, carboplatin, oxaliplatin among most successful treating (Kelland, 2007). Pt introduce covalent adducts DNA which eventually cause death. Tumor treated with therapeutic doses probably die predominantly mitotic catastrophe/necrosis (Borst al, 2001; Brown Attardi, 2005). Attempts link sensitivity prominent (Speirs 2011), however, even though induction high concentrations has been be due cytoplasmic off-target effect (Mandic 2003; Berndtsson 2007; Fayad 2009). cultured cells, other such as staurosporine is characterized early shrinkage denominated decrease (AVD) followed hallmarks like activation caspases fragmentation. AVD could inhibited blockers ubiquitously expressed (also known VSOR or VSOAC) (Maeno 2000; Ise 2005; Okada 2006; Lang Hoffmann, 2012). Being closed under resting opens upon releases chloride osmolytes course regulatory (RVD). was attributed 2000). However, substantiate all non-specific, controversial (Orlov 2013). biophysically physiologically decades, failure identify underlying (Okada, 1997; Pedersen precluded conclusive genetic biochemical studies. Only recently, heteromers identified essential components. obligatory (Qiu 2014; 2014), it needs at least one homolog (LRRC8B, LRRC8C, LRRC8E) mediate volume-activated currents (ICl,vol) release taurine (Voss 2014). weak homology pannexins assemble hexameric (Abascal Zardoya, formation different indicates there several vary properties tissue distribution. For instance, might specify channel's preference over vice versa. Such scenario would support contentious (Lambert 1994; Stutzin 1999; Shennan, 2008) molecularly distinct postulated volume-stimulated osmolyte/anion VSOAC (Jackson Strange, 1993). impact specific VRAC's not yet investigated. An unbiased genomic screen now revealed either two subunits, against carboplatin cisplatin. finding can largely explained unsuspected transport. transport required cisplatin/carboplatin. Exposure additional, uptake-independent, AVD-related apoptosis. Moreover, lacking showed reduced regulation. uncovers novel resistance, identifies LRRC8A/LRRC8D-containing channels, reveals differences pharmacology between differently composed VRACs. Results genomewide mediators To genes affecting platinum sensitivity, we performed loss-of-function screens haploid KBM7 subjected insertional mutagenesis using gene-trap virus (Carette 2009) (Fig 1A). Cells resisting exposure 7 μM three weeks significant enrichment insertions 1B Appendix Table S1). Most sense localized introns upstream ORF-containing exon 3 1C). These positions consistent gene-inactivating mutations. Two LRRC8D-deficient clones, display blasticidin (Lee 2014) lack protein EV1), indeed resistant larger compound 1D S2). Likewise, KBM7-derived HAP1 2011) oxaliplatin, when disrupted EV2). genes, affected carbo- achieved patients. Figure 1. Loss-of-function LRCC8A Outline screen. Genes enriched carboplatin-selected population compared unselected control cells. Circles represent their size corresponds number independent population. ranked x-axis based chromosomal position. Location insertion sites (red arrowheads). White boxes indicate 5′- 3′-untranslated regions, black coding sequence exons 4 (LRRC8A) (LRRC8D). Loss causes oxaliplatin. Survival parental, vector-transduced, GT1 GT2 exposed 96 h increasing corresponding IC50 values 95% confidence interval (CI) given S2. Data presented mean ± SEM. Download figure PowerPoint Click here expand figure. EV1. expression lines A–C. Western blot showing (A), HEK (B), HCT116 (C) lines, knockout lines. Tubulin actin loading control. Note virtually LRRC8E, explaining inactivation ICl,vol clamped voltages 3B). Notice changes apparent sizes (prominently seen HCT cells) because LRRC8B E need leave ER therefore fully glycosylated absence. LRRC8D1−/− LRRC8D2−/− denote clones. EV2. Increased LRRC8A−/− LRRC8D−/− Clonogenic growth LRRC8A− LRRC8D− WT indicated days. Surviving colonies formalin-fixed stained crystal violet. optical absorption determined 590 nm after extracting dye 10% acetic acid. SEM (n = 6). CI, interval. Low correlates survival drug-treated ovarian patients determine whether affect chemotherapy patients, examined Genome Atlas (TCGA) data collection who drugs. analyzed low versus remaining lower tertile distribution expressions cutoff. Whereas had no 2A), gene cancers displayed significantly 2B). received taxane, did provide docetaxel (Appendix Fig corroborate results, investigated derived published Patch (2015). available fewer analysis LRRC8A, correlated modest, 2C D). Thus, 2. shorter grade serous A–D. Differential (A, C) (B, D) extracted TCGA database (http://cancergenome.nih.gov/) B) (2015) (C, As cutoff used. P-values log-rank test. strictly conferred surprising subunit, unlike dispensable Cl− confirmed 3A B, activity. 3. Disruption abolishes blocks A, B. (A) (B) Left panels, example current traces activated hypotonic measured voltage-clamp protocol (A). Dashed zero current. Right averaged current/voltage relationships maximally ICl,vol. Consistent currents, they needed activation, I− > sequence, blocked DCPIB S2A–H). difference fact hardly express LRRC8E EV1) accelerates At potentials +100 mV, inactivated S2I). SEM; n 5–10. C. Dependence (RVD) genes. medium starting t 0, intracellular calcein fluorescence ˜1 semiquantitative measure volume. sixteen wells. view cisplatin-induced subsequent death 2012), explored reliably than AVD. Like RVD similarly impaired LRRC8(B,C,D,E)−/− isoforms B 3C). notwithstanding unchanged amplitudes B; abolished seems unlikely protects toxicity VRAC- AVD-dependent next caspase-3 test subunits. Cisplatin-induced caspase LRRC8A−/−, LRRC8D−/−, LRRC8−/− 4A). explore facilitated during 1 200 (−25%) activity procedure drastically 4B). Swelling-enhanced It reduced, abolished, 4. subunit- osmolarity-dependent continuous presence conditions iso- time WT, obtained clonal each averaged. Caspase 1-h information: SEM, 3–6. *P < 0.05; **P 0.01; ***P 0.001. Similar results experiments. Fold change refers 0. Control experiments hypotonicity per se S4). contrast, staurosporine-induced (where rather unknown reasons) 4C). Since depend compatible hypothesis activation-dependent progression Shimizu 2004). pro-apoptotic stimuli monitored quenching YFP externally added iodide Iodide permeates efficiently hence opening increases rates. slow emergence LRRC8A-dependent component incubation 5A–C) slowly 5E F). Drug-induced small elicited acute 5D). direct comparison slopes, underestimates rates (but preincubation) reflect ensuing S2A E). 5. Activation influx (black ■), (green ▼) halide expressing iodide-sensitive variant periods 0.5 4.5 8.5 before adding extracellular (50 mM final). slopes cisplatin-treated semiquantitatively reflects activation. preincubation large non-specific leaks resulting morbidity. should lead fast pipetting artifact immediately follows (indicated arrows). D. Swelling-induced ■) comparison. final) (230 mOsm solution arrow. E, F. Time (E) (F) (A–C). Averaged maximal eight wells 16 evaluated estimate ▼). observation applied suggested enter Indeed, only conduct ions, compounds glutamate, 1993; Hyzinski-García Lee Qiu Importantly, studies variety have led conclusion involves components: About half passive diffusion plasma membrane via component, (reviewed Gately Howell, accumulation determining extracts various genotypes. (7 μM) drug-resistant clones ~twofold 6A). detail processes saturate up 400 EV3), allowing us use exceeding levels increase assay. When hours roughly 70 respectively 6C (HEK cells), EV4A (HCT cells)). dependence resembled observed (Figs variable first few EV5). studied saline less, detected 6D highlighted dashed line, EV4B). Isotonic appears associated 5) others (Shimizu 2004; Poulsen 2010; Min

Language: Английский

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LRRC8 Proteins Form Volume-Regulated Anion Channels that Sense Ionic Strength

Cell, Journal Year: 2016, Volume and Issue: 164(3), P. 499 - 511

Published: Jan. 1, 2016

Language: Английский

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Transfer of cGAMP into Bystander Cells via LRRC8 Volume-Regulated Anion Channels Augments STING-Mediated Interferon Responses and Anti-viral Immunity

Immunity, Journal Year: 2020, Volume and Issue: 52(5), P. 767 - 781.e6

Published: April 10, 2020

Language: Английский

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Glutamate-Releasing SWELL1 Channel in Astrocytes Modulates Synaptic Transmission and Promotes Brain Damage in Stroke

Neuron, Journal Year: 2019, Volume and Issue: 102(4), P. 813 - 827.e6

Published: April 11, 2019

Language: Английский

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Cardiac Mechano-Gated Ion Channels and Arrhythmias

Circulation Research, Journal Year: 2016, Volume and Issue: 118(2), P. 311 - 329

Published: Jan. 21, 2016

Mechanical forces will have been omnipresent since the origin of life, and living organisms evolved mechanisms to sense, interpret, respond mechanical stimuli. The cardiovascular system in general, heart particular, is exposed constantly changing signals, including stretch, compression, bending, shear. adjusts its performance environment, modifying electrical, mechanical, metabolic, structural properties over a range time scales. Many underlying regulatory processes are encoded intracardially are, thus, maintained even transplant recipients. Although mechanosensitivity rhythm has described medical literature for century, molecular incompletely understood. Thanks modern biophysical technologies, roles cardiac biology being explored more detail, detailed mechanotransduction started emerge. Mechano-gated ion channels mechanoreceptors. They give rise mechano-electric feedback, thought contribute normal function, disease development, and, potentially, therapeutic interventions. In this review, we focus on acute effects electrophysiology, explore candidates observed responses, discuss their pharmaceutical regulation. From this, identify open research questions highlight emerging technologies that may help addressing them.

Language: Английский

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Structure of a volume-regulated anion channel of the LRRC8 family

Nature, Journal Year: 2018, Volume and Issue: 558(7709), P. 254 - 259

Published: May 14, 2018

Language: Английский

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ATP Release Channels

International Journal of Molecular Sciences, Journal Year: 2018, Volume and Issue: 19(3), P. 808 - 808

Published: March 11, 2018

Adenosine triphosphate (ATP) has been well established as an important extracellular ligand of autocrine signaling, intercellular communication, and neurotransmission with numerous physiological pathophysiological roles. In addition to the classical exocytosis, non-vesicular mechanisms cellular ATP release have demonstrated in many cell types. Although large negatively charged molecules cannot diffuse across lipid bilayer plasma membrane, conductive from cytosol into space is possible through ATP-permeable channels. Such channels must possess two minimum qualifications for permeation: anion permeability a ion-conducting pore. Currently, five groups are acknowledged ATP-release channels: connexin hemichannels, pannexin 1, calcium homeostasis modulator 1 (CALHM1), volume-regulated (VRACs, also known volume-sensitive outwardly rectifying (VSOR) channels), maxi-anion (MACs). Recently, major breakthroughs made field by molecular identification CALHM1 action potential-dependent channel taste bud cells, LRRC8s components VRACs, SLCO2A1 core subunit MACs. Here, function roles these summarized, along discussion on future implications understanding

Language: Английский

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