CLC Chloride Channels and Transporters: Structure, Function, Physiology, and Disease

Physiological Reviews, Journal Year: 2018, Volume and Issue: 98(3), P. 1493 - 1590

Published: May 31, 2018

CLC anion transporters are found in all phyla and form a gene family of eight members mammals. Two proteins, each which completely contains an ion translocation parthway, assemble to homo- or heteromeric dimers that sometimes require accessory β-subunits for function. proteins come two flavors: channels anion/proton exchangers. Structures these protein classes surprisingly similar. Extensive structure-function analysis identified residues involved permeation, anion-proton coupling gating led attractive biophysical models. In mammals, ClC-1, -2, -Ka/-Kb plasma membrane Cl − channels, whereas ClC-3 through ClC-7 2Cl /H + -exchangers endolysosomal membranes. Biological roles CLCs were mostly studied but also plants model organisms like yeast Caenorhabditis elegans. have the control electrical excitability, extra- intracellular homeostasis, transepithelial transport, exchangers influence vesicular composition impinge on endocytosis lysosomal The diverse highlighted by human mouse disorders elicited mutations their genes. These pathologies include neurodegeneration, leukodystrophy, mental retardation, deafness, blindness, myotonia, hyperaldosteronism, renal salt loss, proteinuria, kidney stones, male infertility, osteopetrosis. this review, emphasis is laid cell biological organismal mammalian role disease.

Language: Английский

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Extracellular fluid viscosity enhances cell migration and cancer dissemination

Nature, Journal Year: 2022, Volume and Issue: 611(7935), P. 365 - 373

Published: Nov. 2, 2022

Abstract Cells respond to physical stimuli, such as stiffness 1 , fluid shear stress 2 and hydraulic pressure 3,4 . Extracellular viscosity is a key cue that varies under physiological pathological conditions, cancer 5 However, its influence on biology the mechanism by which cells sense changes in are unknown. Here we demonstrate elevated counterintuitively increases motility of various cell types two-dimensional surfaces confinement, dissemination from three-dimensional tumour spheroids. Increased mechanical loading imposed induces an actin-related protein 2/3 (ARP2/3)-complex-dependent dense actin network, enhances Na + /H exchanger (NHE1) polarization through actin-binding partner ezrin. NHE1 promotes swelling increased membrane tension, which, turn, activates transient receptor potential cation vanilloid 4 (TRPV4) mediates calcium influx, leading RHOA-dependent contractility. The coordinated action remodelling/dynamics, NHE1-mediated RHOA-based contractility facilitates enhanced at viscosities. Breast pre-exposed acquire TRPV4-dependent memory transcriptional control Hippo pathway, migration zebrafish, extravasation chick embryos lung colonization mice. Cumulatively, extracellular regulates both short- long-term cellular processes with pathophysiological relevance biology.

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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Chemical and Biomolecular Strategies for STING Pathway Activation in Cancer Immunotherapy

Chemical Reviews, Journal Year: 2022, Volume and Issue: 122(6), P. 5977 - 6039

Published: Feb. 2, 2022

The stimulator of interferon genes (STING) cellular signaling pathway is a promising target for cancer immunotherapy. Activation the intracellular STING protein triggers production multifaceted array immunostimulatory molecules, which, in proper context, can drive dendritic cell maturation, antitumor macrophage polarization, T priming and activation, natural killer vascular reprogramming, and/or death, resulting immune-mediated tumor elimination generation immune memory. Accordingly, there significant amount ongoing preclinical clinical research toward further understanding role surveillance as well development modulators strategy to stimulate immunity. Yet, efficacy agonists limited by many drug delivery pharmacological challenges. Depending on class agonist desired administration route, these may include poor stability, immunocellular toxicity, immune-related adverse events, or lymph node targeting retention, low uptake delivery, complex dependence magnitude kinetics signaling. This review provides concise summary pathway, highlighting recent biological developments, immunological consequences, implications delivery. also offers critical analysis an expanding arsenal chemical strategies that are being employed enhance efficacy, safety, utility lastly draws attention several opportunities therapeutic advancements.

Language: Английский

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Semiconducting Photothermal Nanoagonist for Remote-Controlled Specific Cancer Therapy

Nano Letters, Journal Year: 2018, Volume and Issue: 18(2), P. 1498 - 1505

Published: Jan. 17, 2018

Nanomedicine have shown success in cancer therapy, but the pharmacological actions of most nanomedicine are often nonspecific to cells because utilization therapeutic agents that induce cell apoptosis from inner organelles. We herein report development semiconducting photothermal nanoagonists can remotely and specifically initiate membrane. The organic comprise polymer nanoparticles (SPNs) capsaicin (Cap) as photothermally responsive nanocarrier agonist for activation transient receptor potential cation channel subfamily V member 1 (TRPV1), respectively. Under multiple NIR laser irradiation at time scale seconds, repeatedly locally release Cap multiply activate TRPV1 channels on cellular membrane; cumulative effect is overinflux ions mitochondria followed by induction TRPV1-postive cells. Multiple essential such a death both vitro vivo free simple Cap-encapsulated fail do so. triggered also ensures high local concentration tumor site, permitting specific therapy low systemic administration dosage. Our study thus demonstrates first example ion-channel-specific remote-controlled drug-delivery system therapy.

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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Lipid peroxidation increases membrane tension, Piezo1 gating, and cation permeability to execute ferroptosis

Current Biology, Journal Year: 2023, Volume and Issue: 33(7), P. 1282 - 1294.e5

Published: March 9, 2023

The ongoing metabolic and microbicidal pathways that support protect cellular life generate potentially damaging reactive oxygen species (ROS). To counteract damage, cells express peroxidases, which are antioxidant enzymes catalyze the reduction of oxidized biomolecules. Glutathione peroxidase 4 (GPX4) is major hydroperoxidase specifically responsible for reducing lipid peroxides; this homeostatic mechanism essential, its inhibition causes a unique type lytic cell death, ferroptosis. mechanism(s) lead to lysis in ferroptosis, however, unclear. We report peroxides formed during ferroptosis accumulate preferentially at plasma membrane. Oxidation surface membrane lipids increased tension on led activation Piezo1 TRP channels. Oxidized membranes thus became permeable cations, ultimately leading gain Na+ Ca2+ concomitant with loss K+. These effects were reduced by deletion completely inhibited blocking cation channel conductance ruthenium red or 2-aminoethoxydiphenyl borate (2-APB). also found oxidation depressed activity Na+/K+-ATPase, exacerbating dissipation monovalent gradients. Preventing changes content attenuated Altogether, our study establishes permeability cations critical step execution identifies Piezo1, channels, Na+/K+-ATPase as targets/effectors death.

Language: Английский

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Passive coupling of membrane tension and cell volume during active response of cells to osmosis

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(47)

Published: Nov. 16, 2021

Significance Tension is the force-opposing stretch of lipid membranes. It controls cell functions involving Membranes rupture above a tension threshold, causing death if not properly buffered. However, how membrane quantitatively regulated unknown because it difficult to measure. Using fluorescent probe, we explored coupling between and volume changes during osmosis. This described by an equilibrium theory linking folding unfolding membrane. nevertheless actively components such as cytoskeleton, ion transporters, mTOR pathways. Our results highlight that regulation homeostasis are independent from their coupling.

Language: Английский

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Overview of the vital roles of macro minerals in the human body

Journal of Trace Elements and Minerals, Journal Year: 2023, Volume and Issue: 4, P. 100076 - 100076

Published: June 1, 2023

Macro minerals, also known as macro elements, are minerals that required in large amounts the human body. part of biological structure body, play an important role metabolic processes, and participate almost all processes occur can be toxic if consumed quantities for extended period. There is some evidence to suggest calcium intake may associated with a lower risk obesity. However, relationship between obesity not well understood, more research needed fully understand link. Calcium has been studied its potential development certain types cancer, specifically colorectal breast prostate cancer. higher A deficiency macroelement refers lack one or essential by humans. Macroelement deficiencies lead various health problems, such anemia, osteoporosis, muscle weakness, corrected. The macroelements blood cause many chronic diseases. Hormonal changes resulting from have consequences weight gain, obesity, increased cancer future. It maintain balanced diet ensure adequate elements.

Language: Английский

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Selective transport of neurotransmitters and modulators by distinct volume-regulated LRRC8 anion channels

Journal of Cell Science, Journal Year: 2017, Volume and Issue: 130(6), P. 1122 - 1133

Published: Feb. 14, 2017

In response to swelling, mammalian cells release chloride and organic osmolytes through volume-regulated anion channels (VRACs). VRACs are heteromers of LRRC8A other LRRC8 isoforms (LRRC8B LRRC8E), which co-expressed in HEK293 most cells. The spectrum VRAC substrates its dependence on particular remains largely unknown. We show that, besides the taurine myo-inositol, transport neurotransmitters glutamate, aspartate γ-aminobutyric acid (GABA) co-activator D-serine. engineered express defined subsets were used elucidate subunit-dependence transport. Whereas LRRC8D was crucial for translocation overall neutral compounds like GABA, sustained positively charged lysine, flux negatively equally well supported by LRRC8E. Disruption LRRC8B or LRRC8C failed decrease rates all investigated substrates, but their inclusion into influenced substrate preference VRAC. This suggested that individual can contain three more different subunits, a conclusion confirmed sequential co-immunoprecipitations. Our work suggests composition-dependent role extracellular signal transduction.

Language: Английский

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