Sphingosine-1-phosphate induces migration of microglial cells via activation of volume-sensitive anion channels, ATP secretion and activation of purinergic receptors

Zahiri, Danyal; Burow, Philipp; Großmann, Claudia; Müller, Christa E.; Klapperstück, Manuela; Markwardt, Fritz

doi:10.1016/j.bbamcr.2020.118915

Cited by 16 publications

(12 citation statements)

References 61 publications

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“…Indeed, S1P in normal isotonic buffer induced DCPIB-sensitive outwardly-rectifying VRAC currents in microglia ( Fig. 2E-2G ) ( 23 ). Further pharmacological studies suggest that S1P-induced VRAC activity in microglia is dependent on S1P receptors (S1PR1 and S1PR2) and the production of reactive oxygen species (ROS), but not Ca 2+ ( Figure S1 ).…”

Section: Resultsmentioning

confidence: 98%

ATP-releasing SWELL1 channel in spinal microglia contributes to neuropathic pain

Chu

Qiu

Yang

et al. 2023

Preprint

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Following peripheral nerve injury, extracellular ATP-mediated purinergic signaling is crucial for spinal cord microglia activation and neuropathic pain. However, the mechanisms of ATP release remain poorly understood. Here, we show that volume-regulated anion channel (VRAC) is an ATP-releasing channel and is activated by inflammatory mediator sphingosine-1-phosphate (S1P) in microglia. Mice with microglia-specific deletion of Swell1 (also known as Lrrc8a), a VRAC essential subunit, had reduced peripheral nerve injury-induced increase in extracellular ATP in spinal cord. The mutant mice also exhibited decreased spinal microgliosis, dorsal horn neuronal hyperactivity, and both evoked and spontaneous neuropathic pain-like behaviors. We further performed high-throughput screens and identified an FDA-approved drug dicumarol as a novel and potent VRAC inhibitor. Intrathecal administration of dicumarol alleviated nerve injury-induced mechanical allodynia in mice. Our findings suggest that ATP-releasing VRAC in microglia is a key spinal cord determinant of neuropathic pain and a potential therapeutic target for this debilitating disease.

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Section: Resultsmentioning

confidence: 98%

ATP-releasing SWELL1 channel in spinal microglia contributes to neuropathic pain

Chu

Qiu

Yang

et al. 2023

Preprint

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“… 14 These effects of LRRC8A depend on the subunit composition ( Lrrc8a-e ) of the LRRC8A channel. 61 , 62 , 63 , 64 Although investigating the subunit composition of the LRRC8A channel is beyond the scope of this study, it would be of interest to examine it in future studies.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the LRRC8A channel promotes microglia/macrophage phagocytosis and improves outcomes after intracerebral hemorrhagic stroke

et al. 2022

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“…They are considered to be crucial regulators of the cancer cell growth and survival via the activation of key pathway clusters, such as Ras/Erk and PI3K/Akt [ 18 , 22 ]. It was reported that S1P-induced release of ATP via VRACs formed an autocrine link between inflammatory sphingolipid and purinergic signaling in RAW macrophages [ 27 ] and BV-2 microglia [ 28 ]. In these cells, it was suggested that Gi/o-coupled S1PR1 and rearrangement of the actin cytoskeleton were involved in VRAC activation with S1P.…”

Section: Discussionmentioning

confidence: 99%

Sphingosine-1-Phosphate Induces ATP Release via Volume-Regulated Anion Channels in Breast Cell Lines

Furuya

Harai

Kobayashi

et al. 2021

Life

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High interstitial level of ATP and its lysate adenosine in the cancer microenvironment are considered a halo mark of cancer. Adenosine acts as a strong immune suppressor. However, the source of ATP release is unclear. We clarified the release of ATP via volume-regulated anion channels (VRACs) in breast cell lines using an ATP luminescence imaging system. We detected a slowly rising diffuse pattern of ATP release that was only observed in undifferentiated cells, not in differentiated primary cultured cells. This was confirmed by suppression with DCPIB, a blocker of VRACs, and shRNA for LRRC8A, an indispensable subunit of VRACs. We herein demonstrated that the inflammatory mediator sphingosine-1-phosphate (S1P), which exists abundantly in the cancer microenvironment, induced a diffuse pattern of ATP release isovolumetrically. The response was dose-dependent and suppressed by the knock-down of LRRC8A. It was also suppressed by blockers of S1P receptor 1 and 2 (W146 and JTE013, respectively). RTqPCR demonstrated the prominent presence of S1PR1 and S1PR2 mRNAs. We discussed the roles of S1P-induced ATP release in the cancer microenvironment.

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Sphingosine-1-phosphate induces migration of microglial cells via activation of volume-sensitive anion channels, ATP secretion and activation of purinergic receptors

Cited by 16 publications

References 61 publications

ATP-releasing SWELL1 channel in spinal microglia contributes to neuropathic pain

ATP-releasing SWELL1 channel in spinal microglia contributes to neuropathic pain

Inhibition of the LRRC8A channel promotes microglia/macrophage phagocytosis and improves outcomes after intracerebral hemorrhagic stroke

Sphingosine-1-Phosphate Induces ATP Release via Volume-Regulated Anion Channels in Breast Cell Lines

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