Structural insights into anion selectivity and activation mechanism of LRRC8 volume-regulated anion channels

Liu, Heng; Polovitskaya, Maya M.; Yang, Linlin; Li, Meiling; Li, Hongyue; Han, Zhen; Wu, Jian; Zhang, Qiansen; Jentsch, Thomas J.; Liao, Jun

doi:10.1016/j.celrep.2023.112926

Cited by 6 publications

(5 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…LRRC8 proteins are made up of four transmembrane segments and a C-terminal leucine-rich repeat domain. The N-terminal domain was recently found to fold back into the pore from the cytoplasm, taking part in determining ion selectivity and possibly gating [ 20 ]. The precise proportions and arrangement of subunits needed to create functional LRRC8 heteromers have not yet been fully discovered.…”

Section: Introductionmentioning

confidence: 99%

Interactomic exploration of LRRC8A in volume-regulated anion channels

Carpanese,

Festa,

Prosdocimi

et al. 2024

Cell Death Discov.

View full text Add to dashboard Cite

Ion channels are critical in enabling ion movement into and within cells and are important targets for pharmacological interventions in different human diseases. In addition to their ion transport abilities, ion channels interact with signalling and scaffolding proteins, which affects their function, cellular positioning, and links to intracellular signalling pathways. The study of “channelosomes” within cells has the potential to uncover their involvement in human diseases, although this field of research is still emerging. LRRC8A is the gene that encodes a crucial protein involved in the formation of volume-regulated anion channels (VRACs). Some studies suggest that LRRC8A could be a valuable prognostic tool in different types of cancer, serving as a biomarker for predicting patients’ outcomes. LRRC8A expression levels might be linked to tumour progression, metastasis, and treatment response, although its implications in different cancer types can be varied. Here, publicly accessible databases of cancer patients were systematically analysed to determine if a correlation between VRAC channel expression and survival rate exists across distinct cancer types. Moreover, we re-evaluated the impact of LRRC8A on cellular proliferation and migration in colon cancer via HCT116 LRRC8A-KO cells, which is a current topic of debate in the literature. In addition, to investigate the role of LRRC8A in cellular signalling, we conducted biotin proximity-dependent identification (BioID) analysis, revealing a correlation between VRAC channels and cell-cell junctions, mechanisms that govern cellular calcium homeostasis, kinases, and GTPase signalling. Overall, this dataset improves our understanding of LRRC8A/VRAC and explores new research avenues while identifying promising therapeutic targets and promoting inventive methods for disease treatment.

show abstract

Section: Introductionmentioning

confidence: 99%

Interactomic exploration of LRRC8A in volume-regulated anion channels

Carpanese,

Festa,

Prosdocimi

et al. 2024

Cell Death Discov.

View full text Add to dashboard Cite

show abstract

“…This hypothesis is consistent with a recent study showing that VRAC contributed to ischemic brain injury via the mechanism other than VRAC-mediated glutamate release considering that LRRC8A as an essential component of VRAC, played a regulatory role in signaling pathway 30 . DCPIB, as a speci c blocker of LRRC8A-dependent VRAC inhibited VRAC by binding the N-terminal arginine residue of this helix (R103) of LRRC8A, as a cork-in-bottle mechanism 31 . DCPIB-bound LRRC8A apparently caused correlative movement of the linker region and membrane-proximal C-terminal leucinerich repeat domain (LRRD) 32 which might provide docking surfaces for protein-protein interactions such as NADPH oxidase and GRB2, for signaling to various protein kinases [33][34][35] .…”

Section: Discussionmentioning

confidence: 99%

Volume regulated anion channel blocker, DCPIB modulates microglial M1/M2 polarization via MAPK pathway and attenuates oxidative stress after AIS

Cao,

Guo,

Yang

et al. 2024

Preprint

View full text Add to dashboard Cite

Microglia play a central role in maintenance of brain homeostasis. Microglial polarization plays an important role in the recovery of homeostasis after acute ischemic stroke (AIS). DCPIB, as a blocker of volume-regulated ion channel plays an important role in maintaining intracellular homeostasis. But the relationship between DCPIB and microglial M1/M2 polarization is currently unclear. This study is to investigate the relationship between DCPIB and microglial M1/M2 polarization after AIS. C57BL/6 mice were subjected to transient middle cerebral artery occlusion (tMCAO). DCPIB was given within 5 min after reperfusion. Behavior assessments were conducted at 1, 3, and 7 days after tMCAO. Pathological injuries were evaluated by TTC, HE and Nissl staining and immunofluorescence co-staining (IFC). The phenotypic variations of microglia were examined by IFC. The levels of inflammatory cytokines were analyzed by RT-PCR and ELISA. In mice tMCAO model, DCPIB remarkably reduced mortality, pathological injury and improved behavioral performance and alleviated. DCPIB significantly inhibited inflammatory response, promoted the conversion of M1 microglia to the M2 via MAPK pathway and protected neurons from microglia-mediated inflammatory response. In addition, it was found that DCPIB inhibited oxidative stress after AIS. In conclusions, DCPIB attenuates ischemia-reperfusion injury via regulating microglial M1/M2 polarization and oxidative stress.

show abstract

“…In addition, DCPIB markedly affected the interaction of LRRC8A and S1PR1. DCPIB, as a speci c blocker of VRAC inhibited VRAC by binding the N-terminal arginine residue of this helix (R103) of LRRC8A, as a cork-in-bottle mechanism [42]. DCPIB-bound LRRC8A apparently caused correlative movement of the linker region and membrane-proximal LRRD [43].…”

Section: Discussionmentioning

confidence: 99%

LRRC8A contributes to neuroinflammation after acute ischemic stroke by interacting with S1PR1 regulating MAPK signal pathway

Cao,

Guo,

Yang

et al. 2023

Preprint

View full text Add to dashboard Cite

Objective and design: Neuroinflammation exerts important roles in the progression of acute ischemic stroke (AIS). LRRC8A, an essential component of volume-regulated anion channel (VRAC) is expressed predominantly in central nervous system. The aim of this study is to investigate the role of LRRC8A in microglia-mediated neuroinflammation after AIS and the underlying mechanism. Materials and methods TTC assay, HE and Nissl staining, RT-PCR, ELISA assay, flow cytometry, Western blot (WB) and immunofluorescence were used to detect the effect of DCPIB on brain injury, neuroinflammation after AIS. Concomitantly, immunofluorescence, FLIM-FRET, and co-immunoprecipitation were used to examine the interplays between LRRC8A and S1P receptor-1(S1PR1). Results In mice tMCAO/R model, the administration of LRRC8A-dependent VRAC blocker DCPIB remarkably increased the survival rate and effectively reduced neuronal injury. In addition, DCPIB markedly reversed microglia polarization toward the M1 phenotype and enhanced M2 phenotype. More importantly, LRRC8A physically interacted with S1PR1 via C-terminal leucine-rich repeat domain (LRRD) and DCPIB weakened their interaction. Meanwhile, DCPIB also eliminated the activation MAPK pathway mediated by S1PR1. Conclusions The present study revealed a novel regulatory role of LRRC8A in regulating microglia-mediated neuroinflammation through interacting with S1PR1 by LRRD and elucidated a molecular mechanism for the effects of DCPIB on microglia polarization.

show abstract

Structural insights into anion selectivity and activation mechanism of LRRC8 volume-regulated anion channels

Cited by 6 publications

References 71 publications

Interactomic exploration of LRRC8A in volume-regulated anion channels

Interactomic exploration of LRRC8A in volume-regulated anion channels

Volume regulated anion channel blocker, DCPIB modulates microglial M1/M2 polarization via MAPK pathway and attenuates oxidative stress after AIS

LRRC8A contributes to neuroinflammation after acute ischemic stroke by interacting with S1PR1 regulating MAPK signal pathway

Contact Info

Product

Resources

About