Activation of ATP Secretion via Volume-Regulated Anion Channels by Sphingosine-1-Phosphate in Raw Macrophages

Burow, Philipp; Klapperstück, Manuela; Markwardt, Fritz

doi:10.1016/j.bpj.2014.11.2410

Cited by 6 publications

(8 citation statements)

References 80 publications

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“…The mechanisms by which astrocytes release neurotransmitters include vesicle exocytosis, reversal of transporters that normally remove neurotransmitters from the extracellular space and channel-like processes (Hamilton and Attwell, 2010;Montero and Orellana, 2015). Whereas VRAC/ VSOAC has been implicated in the swelling-activated release of taurine, glutamate, aspartate and D-serine (Rosenberg et al, 2010), its ability to release ATP is debated (Burow et al, 2015;Hazama et al, 1999;Hisadome et al, 2002) and might occur only at extreme levels of hypotonic swelling (Gaitán-Peñas et al, 2016). Another, molecularly unidentified maxi-anion channel may rather mediate swelling-induced ATP release (Sabirov et al, 2016).…”

Section: Vracs In the Release Of Neurotransmittersmentioning

confidence: 99%

“…Although LRRC8D-containing VRACs also transport glutamate, the low brain expression of LRRC8E may serve to minimize deleterious effects of this excitatory neurotransmitter during volume regulation or other processes that require VRAC opening. VRACs may also be activated without an increase of cell volume by several signaling molecules (Akita and Okada, 2011;Burow et al, 2015;HyzinskiGarcía et al, 2014;Mongin and Kimelberg, 2002) and in the course of apoptosis (Planells-Cases et al, 2015). If VRACs display low basal transport activity (Planells-Cases et al, 2015), they might also contribute to ambient (extracellular, extrasynaptic) GABA that has been controversially attributed to a bestrophin-mediated release from astrocytes (Diaz et al, 2011;Lee et al, 2010).…”

Section: Vracs In the Release Of Neurotransmittersmentioning

confidence: 99%

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

Lutter

Ullrich

Lueck

et al. 2017

Journal of Cell Science

120

182

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

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Section: Vracs In the Release Of Neurotransmittersmentioning

confidence: 99%

Section: Vracs In the Release Of Neurotransmittersmentioning

confidence: 99%

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

Lutter

Ullrich

Lueck

et al. 2017

Journal of Cell Science

120

182

View full text Add to dashboard Cite

show abstract

“…VRACs are activated not only by hypotonic stress but also isovolumetrically by various intracellular factors. The inflammatory mediator sphingosine-1-phosphate (S1P) was reported to activate VRACs (Burow P et al, 2015). The application of S1P (100 nM-1 μM) induced the release of ATP with a slowly rising and diffuse pattern in MCF7 cells, which had a comparable amplitude to but declined somewhat faster in comparison to the response to 30% hypotonic stimulation (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, it was concluded that VRACs contributed to the diffuse release of ATP by hypotonic stress in breast cell lines. VRACs facilitate the passage of various substances, including ATP (Hisadome K et al, 2002; Burow P et al, 2015; Gaitán-Peñas H et al, 2016), glycine, aspartate, glutamate, GABA, taurine, myo-inositol and lactate in addition to Cl - (Lutter D et al, 2017; Schober AL et al, 2017). It is debatable whether or not VRACs are a pathway of ATP release (Sabirov RZ and Okada Y, 2005; Liu HT et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Hypo-osmotic Stress Induces ATP Release via Volume-regulated Anion Channels in Undifferentiated Mammary Cells

Furuya

Takahashi

Hirata

et al. 2021

Preprint

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The high interstitial ATP concentration in the cancer microenvironment is a major source of adenosine, which acts as a strong immune suppressor. However, the source of ATP release has not been elucidated. We measured the ATP release during hypotonic stress using a real-time ATP luminescence imaging system in primary cultured mammary cells and in breast cell lines. In primary cultured cells, ATP was intermittently released with transient-sharp peaks, while in breast cell lines ATP was released with a slowly rising diffuse pattern. The diffuse ATP release pattern was changed to a transient-sharp pattern by cholera toxin treatment and the reverse change was induced by transforming growth factor (TGF) β treatment. DCPIB, an inhibitor of volume-regulated anion channels (VRACs), only suppressed the diffuse pattern. The inflammatory mediator sphingosine-1-phosphate (S1P) induced a diffuse ATP release pattern isovolumetrically. The knockdown of A isoform of leucine-rich repeat-containing protein 8 (LRRC8A), the essential molecular entity of VRACs, using shRNA suppressed the diffuse pattern. These results suggest that abundantly expressed VRACs are a conduit of ATP release in undifferentiated cells, including cancer cells.

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“…After establishing the dominance of the LRRC8A:C cGAMP import pathway observed in TIME cells, we next wanted to identify chemical tools to regulate its function. VRAC has been shown to be activated downstream of sphingosine-1-phosphate (S1P) signaling to one of its G protein-coupled receptors, S1PR1 (Burow et al, 2014). In addition, endothelial cells are exposed to high S1P levels in the blood under physiological conditions (estimated 1 μM total), and also produce S1P themselves (Cartier and Hla, 2019).…”

Section: Phosphate and Inhibited By Dcpibmentioning

confidence: 99%

The LRRC8A:C Heteromeric Channel Is a cGAMP Transporter and the Dominant cGAMP Importer in Human Vasculature Cells

Wen

et al. 2020

Preprint

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Extracellular 2'3'-cyclic-GMP-AMP (cGAMP) is an immunotransmitter secreted by cancer cells and taken up by host cells to activate the anti-cancer STING pathway. No cGAMP exporter has been identified, and SLC19A1, a recently identified cGAMP importer, does not account for the import activity in most cell types. Here, we identify the LRRC8A:C heteromeric channel, a volume-regulated anion channel (VRAC), as a cGAMP transporter. This channel mediates cGAMP import or export depending on the cGAMP chemical gradient, and channel activation or inhibition modulates cGAMP transport. Other 2'3'-cyclic dinucleotides are also transported by LRRC8A:C channels, including the investigational cancer therapeutic ADU-S100. Furthermore, we demonstrate that the LRRC8A-containing channel is the dominant cGAMP importer in primary human vasculature cells. Given tumor vasculature's regulation of immune infiltration and its disruption in response to STING agonists, we have uncovered a leading molecular mechanism for extracellular cGAMP signaling in this important anticancer target.

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Activation of ATP Secretion via Volume-Regulated Anion Channels by Sphingosine-1-Phosphate in Raw Macrophages

Cited by 6 publications

References 80 publications

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

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

Hypo-osmotic Stress Induces ATP Release via Volume-regulated Anion Channels in Undifferentiated Mammary Cells

The LRRC8A:C Heteromeric Channel Is a cGAMP Transporter and the Dominant cGAMP Importer in Human Vasculature Cells

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