Swelling activated Cl- channels in microglia

Schlichter, Lyanne C.; Mertens, Timothy Edward; Liu, Baosong

doi:10.4161/chan.5.2.14310

Cited by 34 publications

(16 citation statements)

References 48 publications

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“…In all cases we found that release of the radiotracer was completely suppressed with DCPIB, strongly suggesting that VRAC is involved. These data are consistent with two electrophysiology reports in primary and immortalized microglia, which estimated the relative permeability for glutamate and aspartate to be 0.12–0.18 and 0.22, respectively, as normalized to Cl − permeability [53, 185]. In another more recent study, we measured d -[ 3 H]aspartate release in microglial cells during the ATP stimulated migration, and found that chemotaxis also causes the DCPIB-sensitive efflux of excitatory amino acids [48].…”

Section: Common and Unique Roles Of Vrac Within The Brainsupporting

confidence: 91%

“…Consequently, this inhibitor became the staple for probing VRAC functions in cells, more complex experimental systems, and in vivo . In the CNS, this agent was found to block VRAC in astrocytes [2, 119], neurons and neuroblastoma cells [35, 78], and microglial cells [74, 185]. Furthermore, DCPIB potently protected the brain against ischemic damage in a rodent model of stroke [215].…”

Section: Vrac Pharmacology In the Context Of Probing Its Biological Fmentioning

confidence: 99%

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Volume-regulated anion channel—a frenemy within the brain

Mongin

2015

Pflugers Arch - Eur J Physiol

115

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Volume regulated anion channel (VRAC) is a ubiquitously expressed yet highly enigmatic member of the superfamily of chloride/anion channels. It is activated by cellular swelling and mediates regulatory cell volume decrease in a majority of vertebrate cells, including those in the central nervous system (CNS). In the brain, besides its crucial role in cellular volume regulation, VRAC is thought to play a part in cell proliferation, apoptosis, migration, and release of physiologically active molecules. Although these roles are not exclusive to the CNS, the relative significance of VRAC in the brain is amplified by several unique aspects of its physiology. One important example is contribution of VRAC to release of the excitatory amino acid neurotransmitters, glutamate and aspartate. This latter process is thought to have impact on both normal brain functioning (such as astrocyte-neuron signaling) and neuropathology (via promoting the excitotoxic death of neuronal cells in stroke and traumatic brain injury). In spite of much work in the field the molecular nature of VRAC remained unknown until less than two years ago. Two pioneer publications identified VRAC as the hetero-hexamer formed by the leucine-rich repeat-containing 8 (LRRC8) proteins. These findings galvanized the field and are likely to result in dramatic revisions to our understanding of the place and role of VRAC in the brain, as well as other organs and tissues. The present review briefly recapitulates critical findings in the CNS, and focuses on anticipated impact on the LRRC8 discovery on further progress in neuroscience research.

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Section: Common and Unique Roles Of Vrac Within The Brainsupporting

confidence: 91%

Section: Vrac Pharmacology In the Context Of Probing Its Biological Fmentioning

confidence: 99%

Volume-regulated anion channel—a frenemy within the brain

Mongin

2015

Pflugers Arch - Eur J Physiol

115

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“…More recently, the same concentration has been shown to inhibit ICl swell in microglia (Schlichter et al ., 2011) and reduce regulatory volume decrease in bovine ciliary epithelium (Do et al ., 2006). …”

Section: Flufenamic Acid As An Ion Channel Modulatormentioning

confidence: 96%

Flufenamic acid as an ion channel modulator

Guinamard

Simard

Negro

2013

Pharmacology & Therapeutics

125

113

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Flufenamic acid has been known since the 1960s to have anti-inflammatory properties attributable to the reduction of prostaglandin synthesis. Thirty years later, flufenamic acid appeared to be an ion channel modulator. Thus, while its use in medicine diminished, its use in ionic channel research expanded. Flufenamic acid commonly affects non-selective cation channels and chloride channels, but also modulates potassium, calcium and sodium channels with effective concentrations ranging from 10-6 M in TRPM4 channel inhibition to 10-3 M in two-pore outwardly rectifying potassium channel activation. Because flufenamic acid effects develop and reverse rapidly, it is a convenient and widely used tool. However, given the broad spectrum of its targets, experimental results have to be interpreted cautiously. Here we provide an overview of ion channels targeted by flufenamic acid to aid in interpreting its effects at the molecular, cellular, and systems levels. If it is used with good practices, flufenamic acid remains a useful tool for ion channel research. Understanding the targets of FFA may help reevaluate its physiological impacts and revive interest in its therapeutic potential.

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“…Since phagocytosis leads to cell swelling, we focused in the present study on swelling activated Cl - -current (I Cl, swell ). Activation of I Cl, swell is due to an osmotic imbalance, like hypotonic extracellular or hypertonic intracellular conditions [8,32]. However, a Cl - -conductance with a similar electrophysiological and pharmacological signature is also activated in normotonic conditions via an increase in intracellular Ca 2+ or cAMP and elevated PKA activity or stimulation of exchange proteins directly activated by cAMP (Epac) [15,21,33,34,35,36].…”

Section: Discussionmentioning

confidence: 99%

Chloride Channel Blockers Suppress Formation of Engulfment Pseudopodia in Microglial Cells

Harl

Schmölzer

Jakab

et al. 2013

Cell Physiol Biochem

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Background/Aims: Phagocytosis depends on the formation of engulfment pseudopodia surrounding the target. We tested in microglia, monocyte-derived cells in the brain, whether a swelling-activated Cl^--current (I_Cl,_swell), required for global cell volume (CV) regulation, also contributes to local expansion and retraction of engulfment pseudopodia. Methods: We used scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) to visualize and quantify the uptake of polystyrene microbeads (MBs) by microglial cells. Flow cytometry was used for cell volume measurments and I_Cl,_swell was measured by whole-cell patch clamp. Results: We found that exposure of microglial BV-2 cells to MBs in Cl^--free extracellular solution attenuated MB uptake and that the Cl^--channel blockers DIOA, flufenamic acid, NPPB and DCPIB suppressed the uptake of MBs in BV-2 cells and in primary microglial cells. Microglial cells exposed to MBs in the presence of Cl^- channel blockers failed to extend engulfment pseudopodia. We observed that cells containing at least three MBs revealed an about twofold increase in current density of I_{Cl, swell} compared to cells without MB. Osmotic challenges to stimulate global CV regulation before exposure to MBs modulated phagocytosis. Pre-conditioning of cells in hypo- or hypertonic medium for 12-16 hours caused a decrease in MB uptake. Conclusion: These findings indicate that I_Cl,_swell contributes to formation of engulfment pseudopodia and participates in engulfment and particle uptake in microglial cells.

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Swelling activated Cl- channels in microglia

Cited by 34 publications

References 48 publications

Volume-regulated anion channel—a frenemy within the brain

Volume-regulated anion channel—a frenemy within the brain

Flufenamic acid as an ion channel modulator

Chloride Channel Blockers Suppress Formation of Engulfment Pseudopodia in Microglial Cells

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