Affinage

LRRC8A

Volume-regulated anion channel subunit LRRC8A · UniProt Q8IWT6

Length
810 aa
Mass
94.2 kDa
Annotated
2026-04-28
100 papers in source corpus 40 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LRRC8A (SWELL1) is the obligatory pore-forming subunit of the volume-regulated anion channel (VRAC), assembling as hexameric heteromers with LRRC8B–E paralogs whose composition dictates channel inactivation kinetics, substrate selectivity, and modulation by oxidation (PMID:24725410, PMID:24790029, PMID:28841766). Structurally related to connexins, the LRRC8A hexamer forms a transmembrane pore with an extracellular selectivity filter enriched in basic residues and a second cytoplasmic selectivity filter formed by N-terminal extensions; gating is triggered by reduced cytoplasmic ionic strength, which increases N-terminal mobility and dilates pore-surrounding helices (PMID:29769723, PMID:26824658, PMID:37543949). Beyond canonical chloride and organic osmolyte efflux, LRRC8A-containing channels transport cGAMP, glutathione, and glutamate, thereby coupling cell volume sensing to STING-dependent innate immunity, astrocytic glutamatergic signaling, and redox homeostasis (PMID:32277911, PMID:30982627, PMID:31804464). The cytoplasmic leucine-rich repeat domain additionally scaffolds GRB2–Cav1–eNOS and GRB2–JAK2–STAT3 signaling complexes and associates with NADPH oxidase subunits, enabling LRRC8A to regulate insulin–PI3K–AKT signaling in adipocytes, β-cells, skeletal muscle, and endothelium, as well as ROS-dependent vascular contractility and inflammatory gene expression (PMID:28436964, PMID:33629656, PMID:35966575, PMID:27838438).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2003 Medium

    Before LRRC8A's channel identity was known, a dominant-negative C-terminal truncation established that the leucine-rich repeat domain is functionally required for B lymphocyte development, hinting at a signaling-scaffold role.

    Evidence Bone marrow transplantation with forced expression of truncated LRRC8A, flow cytometric assessment of B cell development

    PMID:14660746

    Open questions at the time
    • Single-lab study without independent replication
    • Mechanism linking LRR domain integrity to B cell development was undefined
    • Channel function was not yet attributed to LRRC8A
  2. 2014 High

    Two independent genome-wide RNAi screens converged on LRRC8A as the long-sought essential component of VRAC, and point mutations altering anion selectivity demonstrated it is a pore-forming subunit that must heteromerize with LRRC8B–E to generate native currents.

    Evidence Genome-wide siRNA screens for hypotonicity-induced iodide influx, site-directed mutagenesis affecting selectivity, CRISPR disruption of all five LRRC8 genes with reconstitution

    PMID:24725410 PMID:24790029

    Open questions at the time
    • Subunit stoichiometry unknown
    • No structural model of the channel
    • Mechanism of swelling-induced gating unresolved
  3. 2014 High

    In parallel, LRRC8A was shown to constitutively associate with GRB2–GAB2 and LCK in thymocytes, activating AKT via PI3K; Lrrc8a-knockout mice displayed a severe block in thymic T cell development, establishing a signaling function beyond ion conduction.

    Evidence Co-immunoprecipitation of signaling complex, Lrrc8a−/− mice, bone marrow chimeras, AKT phosphorylation assays

    PMID:24752297

    Open questions at the time
    • Whether the signaling function depends on channel activity or on the LRR scaffold alone was unclear
    • Molecular basis of GRB2–LRRC8A interaction not defined
  4. 2016 High

    Reconstitution of purified LRRC8 complexes into lipid bilayers proved that LRRC8 proteins are sufficient to form the VRAC pore and established that decreased cytoplasmic ionic strength—not just osmotic swelling—directly activates the channel.

    Evidence Native PAGE, lipid bilayer reconstitution with single-channel recording, ionic strength manipulation

    PMID:26824658

    Open questions at the time
    • How ionic strength change is sensed by the protein was unknown
    • Heteromeric stoichiometry in bilayers undefined
  5. 2017 High

    The LRRC8A C-terminal LRR domain was identified as a signaling hub interacting with GRB2–Cav1 to regulate adipocyte insulin–PI3K–AKT2–GLUT4 signaling and with Nox1/p22phox to support TNFα-induced ROS production in vascular smooth muscle, expanding the gene's role to metabolic and inflammatory signaling.

    Evidence Co-immunoprecipitation (SWELL1–GRB2–Cav1), adipose-specific KO mice with metabolic phenotyping; Co-IP of LRRC8A–Nox1–p22phox, siRNA with superoxide and NF-κB readouts

    PMID:27838438 PMID:28436964

    Open questions at the time
    • Whether GRB2 binding and channel activity are interdependent or separable was unresolved
    • Structural basis of LRR–GRB2 interaction not determined
  6. 2017 High

    Systematic isoform-specific knockdown in astrocytes showed that LRRC8A/D heteromers preferentially transport uncharged osmolytes (taurine, myo-inositol) while LRRC8A/C/E heteromers preferentially transport charged species (glutamate/D-aspartate), establishing subunit-dependent substrate selectivity.

    Evidence siRNA knockdown of individual LRRC8 subunits, radiotracer efflux assays for multiple substrates in rat astrocytes

    PMID:28833202

    Open questions at the time
    • Structural basis for isoform-dependent selectivity unknown
    • Whether these preferences hold in non-astrocytic cell types was not tested
  7. 2018 High

    Cryo-EM and X-ray structures revealed LRRC8A assembles as a hexamer with connexin-like transmembrane topology; an extracellular constriction enriched in basic residues forms a selectivity filter, and the N-terminal domain and intracellular TM2–TM3 loop were shown by mutagenesis to line the cytoplasmic pore and control conductance and gating.

    Evidence Cryo-EM and X-ray crystallography of homomeric LRRC8A; SCAM and charge-reversal mutagenesis; domain-swap chimeras with electrophysiology

    PMID:29769723 PMID:29853476 PMID:29925591 PMID:30127360

    Open questions at the time
    • Structures were of homomeric channels; heteromeric architecture remained unknown
    • Gating transition pathway not captured at atomic resolution
  8. 2018 High

    Cell-type-specific knockouts in β-cells established that LRRC8A-dependent VRAC is activated by glucose-induced swelling, depolarizes the β-cell membrane, and is required for first-phase glucose-stimulated insulin secretion and glucose tolerance.

    Evidence β-cell-specific tamoxifen-inducible Lrrc8a KO mice, patch-clamp, calcium imaging, insulin secretion from isolated islets

    PMID:29371604 PMID:29773801

    Open questions at the time
    • Relative contribution of VRAC versus other depolarizing currents in β-cells not quantified
    • Subunit composition of β-cell VRAC not determined
  9. 2019 High

    Cryo-EM in lipid nanodiscs with inhibitor DCPIB showed the drug plugs the extracellular selectivity filter; constricted and expanded conformations revealed coupled dilation of LRR domains and the pore, providing the first structural model of a gating mechanism.

    Evidence Cryo-EM in lipid nanodiscs, DCPIB-bound and apo structures, conformational analysis

    PMID:30775971

    Open questions at the time
    • Full open-state structure not resolved
    • Heteromeric gating conformations unknown
  10. 2019 High

    Astrocyte-specific Swell1 knockout demonstrated that VRAC mediates non-vesicular glutamate release in the brain, modulates presynaptic release probability, and contributes to ischemic brain damage, establishing LRRC8A as a gliotransmitter release pathway.

    Evidence Astrocyte-specific conditional KO, electrophysiology, glutamate release assay, MCAO stroke model

    PMID:30982627

    Open questions at the time
    • Which LRRC8 heteromeric composition dominates in astrocytes in vivo was not determined
    • Contribution relative to other glutamate release mechanisms not fully dissected
  11. 2020 High

    LRRC8A/LRRC8E-containing channels were identified as the primary transport pathway for the immune second messenger cGAMP, linking VRAC to STING-dependent innate immune signaling; this established VRAC as a conduit for signaling molecules beyond simple osmolytes.

    Evidence Biochemical cGAMP transport assay, LRRC8A/E genetic KO, HSV-1 infection model; systematic isoform KO with pharmacological dissection

    PMID:32277911 PMID:33171122

    Open questions at the time
    • Structural basis of cGAMP permeation through the pore not resolved
    • Whether VRAC-mediated cGAMP transport is relevant in all tissue contexts unclear
  12. 2020 High

    LRRC8 channels on lysosomal membranes (Lyso-VRAC) were shown to require a C-terminal dileucine motif for targeting and to facilitate water expulsion via lysosome-derived vacuoles under osmotic, hypoxic, and hypothermic stress, revealing an organellar function beyond the plasma membrane.

    Evidence Lysosome patch-clamp, L706L707A mutagenesis, subcellular fractionation, live-cell imaging

    PMID:33139539

    Open questions at the time
    • Subunit composition of lysosomal VRAC not determined
    • Regulation of Lyso-VRAC gating may differ from plasma membrane VRAC
  13. 2021 High

    Under hypertonic stress, p38–MSK1 phosphorylates LRRC8A at S217, activating Cl− efflux that triggers the WNK–NKCC pathway for regulatory volume increase, revealing the first defined phosphorylation-dependent activation mechanism for VRAC.

    Evidence Genome-wide CRISPR screen, S217A mutagenesis, kinase inhibitor studies, patch-clamp

    PMID:34083438

    Open questions at the time
    • Whether S217 phosphorylation also regulates VRAC under hypotonic conditions was not tested
    • Additional phosphorylation sites and kinases likely exist
  14. 2021 High

    The LRR domain was shown to scaffold GRB2–JAK2 to activate STAT3 signaling in myofibroblasts, promoting fibrotic remodeling after myocardial infarction; endothelial LRRC8A similarly scaffolds GRB2–Cav1–eNOS to regulate AKT-eNOS signaling and blood pressure.

    Evidence Co-IP of LRRC8A–GRB2–JAK2, LRRD deletion mutagenesis, myofibroblast-specific KO; Co-IP of LRRC8A–GRB2–Cav1–eNOS, endothelium-specific KO mice

    PMID:33629656 PMID:35966575

    Open questions at the time
    • Whether LRR-scaffolded signaling requires concurrent channel activity is unclear
    • Structural basis of multivalent LRR–adaptor interactions not determined
  15. 2022 High

    Cryo-EM structures of heterohexameric LRRC8A/C channels revealed a predominant 4A:2C stoichiometry with paired LRRC8A subunits flanking mobile LRRC8C subunits; pore-occluding lipids suggested a lipid-gating mechanism in the closed state.

    Evidence Single-particle cryo-EM with fiducial tagging (human and murine LRRC8A/C), electrophysiological validation

    PMID:36522427 PMID:36928458

    Open questions at the time
    • Structures of other heteromeric combinations (A/D, A/E) remain unsolved
    • Transition from lipid-occluded closed to open state not captured
  16. 2022 High

    SWELL1 polarization to the trailing edge of migrating cells was shown by optogenetics to determine migration direction, and dual NHE1/SWELL1 knockdown inhibited breast cancer extravasation in vivo, linking VRAC to cell motility and metastasis.

    Evidence Optogenetic spatiotemporal control of SWELL1 localization, confined migration assay, in vivo extravasation model

    PMID:36253369

    Open questions at the time
    • Molecular mechanism of SWELL1 polarization unknown
    • Generalizability to non-breast cancer migration contexts not established
  17. 2023 High

    A 2.8-Å cryo-EM structure resolved the LRRC8A N-terminus folding back into the pore to form a second selectivity filter in series with the extracellular one; molecular dynamics simulations showed that low ionic strength increases N-terminal mobility and expands pore helices, providing a unified gating and selectivity model.

    Evidence 2.8-Å cryo-EM, molecular dynamics simulation, functional mutagenesis

    PMID:37543949

    Open questions at the time
    • How this dual-filter model operates in heteromeric channels is not established
    • Direct experimental validation of ionic-strength-sensing residues remains incomplete
  18. 2024 Medium

    Phosphorylation of LRRC8A at S174 was identified as a steady-state checkpoint for VRAC; ATP-evoked K+ efflux reduces S174 phosphorylation, promoting VRAC activation and cGAMP transport in the tumor microenvironment, revealing a second regulatory phosphosite.

    Evidence S174 mutagenesis, K+ efflux manipulation, phosphorylation assay, cGAMP transport assay, MC38 tumor model

    PMID:38847616

    Open questions at the time
    • Kinase responsible for S174 phosphorylation not identified
    • Single-lab finding awaits independent confirmation
    • Interplay between S174 and S217 phosphorylation unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis of gating in native heteromeric channels, how the LRR scaffold coordinates channel-dependent and channel-independent signaling outputs, and the tissue-specific determinants of LRRC8 heteromer assembly.
  • No open-state structure of a heteromeric LRRC8 channel
  • Structural basis of LRR–GRB2/Nox interaction not resolved
  • Mechanisms controlling heteromer stoichiometry and assembly in vivo unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 8 GO:0060090 molecular adaptor activity 4
Localization
GO:0005886 plasma membrane 4 GO:0005764 lysosome 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 3 R-HSA-112316 Neuronal System 2
Partners
CAV1GRB2LRRC8BLRRC8CLRRC8DLRRC8EMPRIPNOX1
Complex memberships
VRAC (LRRC8A/B-E hexameric heteromer)

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 LRRC8A (SWELL1) is an essential obligatory subunit of the volume-regulated anion channel (VRAC); genome-wide siRNA screens identified it as required for hypotonicity-induced iodide influx and VRAC currents; point mutations in SWELL1 alter VRAC anion selectivity, demonstrating it is a pore-forming component. Genome-wide RNAi screen, siRNA knockdown, patch-clamp electrophysiology, site-directed mutagenesis, plasma membrane localization by immunofluorescence Cell High 24725410 24790029
2014 LRRC8A forms obligatory heteromers with other LRRC8 family members (LRRC8B–E); all five LRRC8 genes must be disrupted to abolish VRAC currents, and reconstitution requires co-transfection of LRRC8A with at least one other isoform; isoform combination determines inactivation kinetics. Genomic disruption of LRRC8 genes (CRISPR/siRNA), reconstitution by co-transfection, patch-clamp electrophysiology Science High 24790029
2016 LRRC8 proteins assemble into heterogeneous ~800 kDa complexes; when reconstituted into lipid bilayers, LRRC8 complexes form anion channels activated by osmolality gradients and by low ionic strength in the absence of osmotic gradient, demonstrating that LRRC8 proteins constitute the VRAC pore and that hypotonic stress can activate VRAC through decreased cytoplasmic ionic strength. Native PAGE, lipid bilayer reconstitution, single-channel electrophysiology, ionic strength manipulation Cell High 26824658
2018 Cryo-EM and X-ray crystallography structures of homomeric LRRC8A reveal a hexameric assembly with a transmembrane pore domain structurally related to connexin proteins; the pore is constricted extracellularly by a selectivity filter enriched in basic residues that attract anions electrostatically; the cytoplasmic domain consists of leucine-rich repeats. Cryo-electron microscopy, X-ray crystallography Nature High 29769723
2018 Cryo-EM of human LRRC8A reveals a hexameric assembly with topology similar to gap junction channels; two structural populations (compact and relaxed) suggest the LRR domain is flexible with rigid-body motions implicated in pore opening; the extracellular pore constriction bears conserved polar and charged residues contributing to anion/osmolyte permeability. Single-particle cryo-electron microscopy Nature structural & molecular biology High 30127360
2019 Cryo-EM structures of LRRC8A in lipid nanodiscs with inhibitor DCPIB show DCPIB plugs the extracellular selectivity filter like a cork; constricted and expanded structures reveal coupled dilation of cytoplasmic LRRs and the channel pore, suggesting a gating mechanism; lipid bilayer environment critically influences channel conformation compared to detergent micelles. Single-particle cryo-EM in lipid nanodiscs, inhibitor-bound structure determination eLife High 30775971
2018 The N-terminal stretch preceding the first LRRC8 transmembrane domain lines the cytoplasmic portion of the VRAC pore; substituted-cysteine accessibility and charge-reversal mutagenesis of glutamate 6 demonstrate N termini come close together in the complex and influence VRAC conductance, iodide/chloride permeability, and voltage-dependent inactivation gating. Substituted-cysteine accessibility method (SCAM), charge-reversal mutagenesis (E6C + MTSES), patch-clamp electrophysiology The Journal of biological chemistry High 29925591
2018 The intracellular loop (IL) connecting TM2–TM3 of LRRC8A and extracellular loop 1 (EL1) of LRRC8C/D/E are essential for VRAC activity; a 25-amino-acid sequence unique to LRRC8A IL is sufficient to generate homomeric VRAC activity when inserted into LRRC8C/E; chimeric LRRC8A IL sequences alter anion permeability, rectification, and voltage sensitivity. Domain-swap chimera construction, heterologous expression in LRRC8-null cells, patch-clamp electrophysiology The Journal of general physiology High 29853476
2021 Under hypertonic stress, p38 kinase activates its downstream kinase MSK1, which phosphorylates LRRC8A; this LRRC8A-mediated Cl- efflux activates the WNK kinase pathway, which promotes NKCC-mediated electrolyte influx and regulatory volume increase (RVI). LRRC8A-S217A mutation impairs MSK1-dependent channel activation and reduces RVI and cell survival. Genome-wide CRISPR/Cas9 screen, site-directed mutagenesis (S217A), kinase inhibitor studies, patch-clamp electrophysiology Proceedings of the National Academy of Sciences of the United States of America High 34083438
2023 Cryo-EM structures of heterohexameric LRRC8A:C channels reveal predominant A:C stoichiometry of 4:2; four LRRC8A subunits cluster in pairs in their closed conformation while two LRRC8C subunits show larger flexibility, destabilizing the tightly packed LRRC8A subunits to enhance channel activation; lipids embedded in the pore block ion conduction in the closed state. Single-particle cryo-EM with fiducial-tagging strategy, functional electrophysiological validation Nature structural & molecular biology High 36928458
2022 Cryo-EM structure of murine LRRC8A/C heterohexamers shows predominant 4A:2C arrangement; heterotypic LRR interactions displace subunits from the conduction axis compared to homomers, providing structural basis for altered activation and permeation properties of heteromeric channels. Single-particle cryo-electron microscopy Nature structural & molecular biology High 36522427
2023 A 2.8-Å cryo-EM structure of human LRRC8A shows N-terminal halves fold back into the pore, forming a second selectivity filter that works in series with the extracellular filter to determine ion selectivity; C-terminal halves of N termini interact with intracellular loops critical for activation; molecular dynamics simulations show low ionic strength increases NT mobility and expands pore-surrounding helices. Cryo-EM (2.8 Å), molecular dynamics simulation, functional mutagenesis Cell reports High 37543949
2017 LRRC8A-E heteromeric channels are directly modulated by oxidation of intracellular cysteine residues in a subunit-dependent manner: LRRC8A/E heteromers are dramatically activated (>10-fold) by oxidation, whereas LRRC8A/C and LRRC8A/D heteromers are inhibited; this acts directly on channel proteins, not via regulatory factors. Patch-clamp electrophysiology with fluorescently tagged constitutively active constructs, oxidant treatment (chloramine-T, tBHP) The Journal of physiology High 28841766
2020 LRRC8 proteins localized on lysosome membranes generate Lyso-VRAC currents in response to low cytoplasmic ionic strength; a double-leucine L706L707 motif at the C-terminus of LRRC8A is required for lysosomal targeting; Lyso-VRACs facilitate formation of lysosome-derived vacuoles that expel excess water, and Lyso-VRAC activity is necessary for cell survival under hypoosmotic, hypoxic and hypothermic stresses. Lysosome patch-clamp electrophysiology, mutagenesis of targeting motif (L706L707A), subcellular fractionation, live cell imaging Proceedings of the National Academy of Sciences of the United States of America High 33139539
2017 SWELL1/LRRC8A regulates adipocyte insulin-PI3K-AKT2-GLUT4 signaling, glucose uptake, and lipid content via its C-terminal leucine-rich repeat domain interactions with GRB2 and Cav1; silencing GRB2 in SWELL1-KO adipocytes rescues insulin-pAKT2 signaling; adipose-targeted SWELL1 KO mice show reduced adiposity and impaired glycaemia. Co-immunoprecipitation (SWELL1–GRB2–Cav1), adipocyte patch-clamp, adipose-specific KO mice, glucose uptake assay, AKT2 phosphorylation Nature cell biology High 28436964
2014 LRRC8A constitutively associates with the GRB2-GAB2 complex and lymphocyte-specific protein tyrosine kinase (LCK) in thymocytes; LRRC8A ligation activates AKT via the LCK-ZAP-70-GAB2-PI3K pathway; Lrrc8a-/- mice show markedly reduced AKT phosphorylation in thymus and a severe cell-intrinsic block in early thymic development. Co-immunoprecipitation, flow cytometry, Lrrc8a-/- mice, bone marrow chimeras, AKT phosphorylation assays The Journal of experimental medicine High 24752297
2021 LRRC8A physically interacts with NADPH oxidase subunits Nox2, Nox4, and p22phox via its C-terminal leucine-rich repeat domain (LRRD); this interaction supports angiotensin II-induced ROS production and NADPH oxidase activity; LRRD-mutant LRRC8A fails to interact with Nox subunits and is non-functional in this pathway. Co-immunoprecipitation, immunofluorescence co-localization, LRRD deletion mutagenesis, NADPH oxidase activity assay, AAV9-siRNA knockdown in mice Free radical biology & medicine High 33515753
2016 LRRC8A co-immunoprecipitates with NADPH oxidase 1 (Nox1) and its p22phox subunit in vascular smooth muscle cells; LRRC8A is required for TNFα-induced extracellular superoxide production by Nox1, which is in turn essential for TNFR1 endocytosis and JNK phosphorylation; LRRC8A siRNA inhibits NF-κB activation, iNOS/VCAM expression, and VSMC proliferation. Co-immunoprecipitation, immunostaining co-localization, siRNA knockdown, superoxide production assay, TNFR1 endocytosis assay Free radical biology & medicine High 27838438
2021 LRRC8A regulates myofibroblast transformation and cardiac fibrosis via its LRRD domain directly interacting with GRB2, an adaptor protein associated with tyrosine-phosphorylated JAK2, thereby activating JAK2-STAT3 signaling in response to TGF-β1; myofibroblast-specific Lrrc8a KO attenuates fibrotic remodeling after MI. Co-immunoprecipitation (LRRC8A–GRB2–JAK2), LRRD deletion mutagenesis, myofibroblast-specific conditional KO, RNA-seq Theranostics High 35966575
2021 The endothelial SWELL1/LRRC8A forms a GRB2-Cav1-eNOS signaling complex and regulates AKT-eNOS signaling under basal, stretch, and shear-flow stimulation; endothelium-restricted Lrrc8a KO mice develop hypertension and impaired retinal blood flow. Co-immunoprecipitation (LRRC8A–GRB2–Cav1–eNOS), endothelium-specific KO mice, patch-clamp, shear flow assay eLife High 33629656
2020 LRRC8A/LRRC8E-containing VRACs transport cGAMP and cyclic dinucleotides across the plasma membrane; LRRC8A/SWELL1 is required for STING-dependent IFN responses to extracellular cGAMP; enhancing VRAC activity potentiates cGAMP-mediated STING signaling; Lrrc8e-/- mice have impaired IFN responses and compromised immunity to HSV-1. Biochemical transport assay, electrophysiology, LRRC8A/E genetic knockout, HSV-1 infection model in vivo Immunity High 32277911
2020 LRRC8A heteromers (with LRRC8C and/or LRRC8E) function as cGAMP importers/exporters driven by the cGAMP electrochemical gradient; LRRC8D inhibits cGAMP transport; sphingosine 1-phosphate activates and DCPIB inhibits channel-mediated cGAMP transport; LRRC8A channels are key cGAMP transporters in resting primary human vasculature cells. CRISPR KO of LRRC8 isoforms, cGAMP transport assay, pharmacological activation/inhibition, primary human cell studies Molecular cell High 33171122
2019 Astrocytic VRAC (requiring SWELL1/LRRC8A) mediates non-vesicular glutamate release activated by both cell swelling and receptor stimulation; astrocyte-specific Swell1 KO mice show impaired glutamatergic synaptic transmission, reduced presynaptic release probability, and are protected from ischemic brain damage. Astrocyte-specific Swell1 conditional KO, electrophysiology, glutamate release assay, in vivo stroke model (MCAO) Neuron High 30982627
2018 SWELL1 mediates a glucose-stimulated swelling-activated depolarizing chloride current (ICl,SWELL) in pancreatic β-cells; this contributes to membrane depolarization and VGCC-dependent intracellular calcium signaling; tamoxifen-inducible β-cell-targeted Swell1 KO mice have impaired glucose-stimulated insulin secretion and glucose tolerance. β-cell patch-clamp, β-cell-specific tamoxifen-inducible KO mice, glucose-stimulated insulin secretion assay, calcium imaging Nature communications High 29371604
2018 LRRC8A-dependent VRAC currents are activated by β-cell swelling induced by both hypotonicity and glucose; VRAC depolarizes β-cells to cause electrical excitation; Lrrc8a disruption reduces first-phase glucose-induced insulin secretion without affecting tolbutamide or high-K+ stimulated secretion; β-cell-specific LRRC8A KO mice have impaired glucose tolerance. β-cell-specific LRRC8A KO mice, patch-clamp, calcium imaging, insulin secretion assay from isolated islets Nature communications High 29773801
2020 SWELL1/LRRC8A functionally encodes a swell-activated anion channel in skeletal muscle cells regulating PI3K-AKT, ERK1/2, and mTOR signaling, myoblast fusion and differentiation; LRRC8A overexpression rescues KO myotube formation; skeletal muscle-specific Lrrc8a KO mice have smaller myofibers, reduced muscle force and endurance, with increased adiposity and glucose intolerance on high-fat diet. Skeletal muscle-specific Lrrc8a KO mice, patch-clamp, myoblast differentiation assay, insulin signaling phosphorylation, exercise endurance testing eLife High 32930093
2019 LRRC8/VRAC mediates non-vesicular release of glutamate through a glutamate-permeable channel in astrocytes; both cell swelling and agonist-stimulated receptor activation open LRRC8A-dependent VRAC; LRRC8A knockdown completely abolishes ATP-stimulated release of D-aspartate and taurine from non-swollen astrocytes. siRNA knockdown of LRRC8A, radiotracer efflux assays, HPLC amino acid measurement The Journal of physiology High 25172945
2017 In rat astrocytes, distinct LRRC8A heteromers serve different transport functions: LRRC8A/D-containing channels preferentially mediate release of uncharged osmolytes (taurine, myo-inositol), while LRRC8A/C/E-containing channels preferentially transport charged osmolytes (D-aspartate/glutamate). siRNA knockdown of individual LRRC8 subunits, radiotracer efflux assays for multiple substrates The Journal of physiology High 28833202
2022 SWELL1 polarizes to the cell trailing edge during confined migration; optogenetic spatiotemporal regulation of SWELL1 shows its polarization determines migration direction and efficiency; dual NHE1/SWELL1 knockdown inhibits breast cancer cell extravasation and metastasis in vivo. Live cell imaging, optogenetics (SWELL1 redistribution), confined migration assay, in vivo extravasation/metastasis model, mathematical modeling Nature communications High 36253369
2018 Germ cell-specific disruption of Lrrc8a leads to cytoplasmic swelling of late spermatids, failure to reduce cytoplasm, disorganized mitochondrial sheaths, angulated/coiled flagella, and severely reduced sperm motility, causing male infertility in mice; this occurs in a cell-autonomous manner consistent with impaired volume regulation. Germ cell-specific and Sertoli cell-specific conditional KO mice, electron microscopy, sperm motility analysis, fertility testing The Journal of biological chemistry High 29880644
2019 The LRRC8/VRAC channel is permeable to glutathione (GSH, PGSH/PCl ~0.1); hypotonic LRRC8A-dependent GSH efflux reduces intracellular GSH, modulating ROS levels; LRRC8A siRNA or DCPIB attenuates TGFβ1-induced EMT by controlling GSH/ROS levels. GSH current measurement in HEK293-WT vs LRRC8A-KO cells, DCPIB inhibition, siRNA knockdown, EMT marker assays Cell death & disease Medium 31804464
2021 LRRC8A associates with myosin phosphatase rho-interacting protein (MPRIP) as identified by LRRC8A immunoprecipitation-mass spectrometry; co-localization confirmed by PLA and IP/western; LRRC8A-MPRIP interaction links Nox1-derived ROS to RhoA/ROCK/MYPT1 signaling controlling vascular smooth muscle contractility. Immunoprecipitation-mass spectrometry, proximity ligation assay, IP/western blot, VSMC-specific Lrrc8a KO mice, mesenteric vessel contraction assay FASEB journal Medium 37310356
2022 LRRC8A is essential for VRAC currents in proximal tubules; LRRC8A and LRRC8D are localized to basolateral membranes of proximal tubules; conditional deletion of LRRC8A in proximal tubules or constitutive deletion of LRRC8D causes proximal tubular injury, increased diuresis, and Fanconi-like symptoms, demonstrating VRAC is required for basolateral exit of organic compounds in proximal tubules. Epitope-tagged LRRC8 knock-in mice (localization), tubule-specific conditional KO, urine/serum metabolomics, histology Journal of the American Society of Nephrology High 35777784
2003 A truncated LRRC8A protein (deletion of C-terminal LRRs due to chromosomal translocation) co-expressed with intact LRRC8A inhibits B cell development; forced expression of the truncated LRRC8A in mouse bone marrow inhibits B cell development in transplantation experiments, demonstrating a dominant-negative role for C-terminal LRR integrity in B lymphopoiesis. Bone marrow transplantation, forced expression of truncated LRRC8A, flow cytometry of B cell development The Journal of clinical investigation Medium 14660746
2022 Cryo-EM, molecular docking, and medicinal chemistry show that DCPIB derivatives (SN-401 class) bind the LRRC8A hexameric complex; in vivo, SN-401 restores SWELL1 protein, plasma membrane trafficking, and signaling via SWELL1-dependent mechanisms, improving glycemic control in diabetic mice. Cryo-EM, molecular docking, medicinal chemistry SAR, in vivo murine diabetes model Nature communications High 35145074
2024 ATP-evoked K+ efflux reduces phosphorylation of LRRC8A at S174, promoting VRAC activation and cGAMP transport; S174 phosphorylation acts as a checkpoint for VRAC in steady state; mutagenesis of S174 alters VRAC responsiveness to ATP in the tumor microenvironment. Mutagenesis (S174), K+ efflux manipulation, phosphorylation assay, cGAMP transport assay, MC38 tumor model Journal of immunology Medium 38847616
2019 LRRC8A channel in nodose ganglia neurons is activated by extracellular acid pH (pHo) in addition to hypoosmolarity; acid pH activation involves proton efflux, intracellular alkalinity, and NOX-derived H2O2; VRAC/LRRC8A activation by low pHo reduces neuronal injury during simulated ischemia. Primary nodose neuron culture, Cre-flox KO, shRNA knockdown, CRISPR/Cas9 deletion, patch-clamp, intracellular pH measurement JCI insight Medium 28289711
2019 LRRC8/VRAC channel mediates myoblast differentiation by promoting membrane hyperpolarization early during differentiation, which in turn enables K+ channel activation, increased intracellular Ca2+, and subsequent myogenin expression and myoblast fusion; VRAC acts upstream of K+ channel activation in this differentiation cascade. siRNA knockdown of LRRC8A, pharmacological VRAC inhibition, membrane potential measurement, Ca2+ imaging, myogenin expression assay The Journal of biological chemistry Medium 31387946
2020 LRRC8A is essential for hypotonicity-induced NLRP3 inflammasome activation in macrophages; LRRC8A is dispensable for canonical DAMP-induced NLRP3 activation; this was demonstrated by genetic ablation and pharmacological inhibition. Lrrc8a conditional KO macrophages, VRAC inhibitors, NLRP3 inflammasome activation assay (IL-1β, caspase-1) eLife Medium 33216713
2024 Crystal-induced NLRP3 inflammasome activation in macrophages requires cell volume regulation via LRRC8 anion channels; LRRC8 activation upon MSU/CPP crystal exposure induces ATP release, P2Y receptor activation, and intracellular calcium increase necessary for NLRP3 activation and IL-1β maturation; LRRC8 inhibition abolishes crystal-induced inflammation in vitro and in mouse models. Pharmacological inhibition, genetic silencing, ATP release assay, calcium imaging, mouse gout models Nature communications High 39294178

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC. Science (New York, N.Y.) 511 24790029
2014 SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel. Cell 476 24725410
2020 Transfer of cGAMP into Bystander Cells via LRRC8 Volume-Regulated Anion Channels Augments STING-Mediated Interferon Responses and Anti-viral Immunity. Immunity 240 32277911
2016 LRRC8 Proteins Form Volume-Regulated Anion Channels that Sense Ionic Strength. Cell 208 26824658
2019 Glutamate-Releasing SWELL1 Channel in Astrocytes Modulates Synaptic Transmission and Promotes Brain Damage in Stroke. Neuron 185 30982627
2018 Structure of a volume-regulated anion channel of the LRRC8 family. Nature 153 29769723
2020 LRRC8A:C/E Heteromeric Channels Are Ubiquitous Transporters of cGAMP. Molecular cell 150 33171122
2017 SWELL1 is a regulator of adipocyte size, insulin signalling and glucose homeostasis. Nature cell biology 141 28436964
2012 LRRC8 proteins share a common ancestor with pannexins, and may form hexameric channels involved in cell-cell communication. BioEssays : news and reviews in molecular, cellular and developmental biology 138 22532330
2003 A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans. The Journal of clinical investigation 122 14660746
2014 LRRC8A protein is indispensable for swelling-activated and ATP-induced release of excitatory amino acids in rat astrocytes. The Journal of physiology 113 25172945
2014 Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function. The Journal of experimental medicine 105 24752297
2016 Investigation of LRRC8-Mediated Volume-Regulated Anion Currents in Xenopus Oocytes. Biophysical journal 99 27705766
2018 Cryo-EM structures of the human volume-regulated anion channel LRRC8. Nature structural & molecular biology 95 30127360
2019 Cryo-EM structures of the DCPIB-inhibited volume-regulated anion channel LRRC8A in lipid nanodiscs. eLife 90 30775971
2018 SWELL1 is a glucose sensor regulating β-cell excitability and systemic glycaemia. Nature communications 85 29371604
2018 LRRC8/VRAC anion channels enhance β-cell glucose sensing and insulin secretion. Nature communications 84 29773801
2017 Molecular composition and heterogeneity of the LRRC8-containing swelling-activated osmolyte channels in primary rat astrocytes. The Journal of physiology 83 28833202
2019 A 30-year journey from volume-regulated anion currents to molecular structure of the LRRC8 channel. The Journal of general physiology 81 30651298
2015 VRAC: molecular identification as LRRC8 heteromers with differential functions. Pflugers Archiv : European journal of physiology 70 26635246
2020 LRRC8 family proteins within lysosomes regulate cellular osmoregulation and enhance cell survival to multiple physiological stresses. Proceedings of the National Academy of Sciences of the United States of America 60 33139539
2022 Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis. Nature communications 58 36253369
2015 TMEM16, LRRC8A, bestrophin: chloride channels controlled by Ca(2+) and cell volume. Trends in biochemical sciences 58 26254230
2021 The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function. eLife 57 33629656
2023 Upregulation of LRRC8A by m5C modification-mediated mRNA stability suppresses apoptosis and facilitates tumorigenesis in cervical cancer. International journal of biological sciences 56 36632452
2020 SWELL1 regulates skeletal muscle cell size, intracellular signaling, adiposity and glucose metabolism. eLife 56 32930093
2016 Downregulation of LRRC8A protects human ovarian and alveolar carcinoma cells against Cisplatin-induced expression of p53, MDM2, p21Waf1/Cip1, and Caspase-9/-3 activation. American journal of physiology. Cell physiology 54 26984736
2016 Dual role of LRRC8A-containing transporters on cisplatin resistance in human ovarian cancer cells. Journal of inorganic biochemistry 51 27112899
2017 Comparative Effects of Chloride Channel Inhibitors on LRRC8/VRAC-Mediated Chloride Conductance. Frontiers in pharmacology 49 28620305
2017 Subunit-dependent oxidative stress sensitivity of LRRC8 volume-regulated anion channels. The Journal of physiology 48 28841766
2015 The volume-regulated anion channel is formed by LRRC8 heteromers – molecular identification and roles in membrane transport and physiology. Biological chemistry 48 25868000
2018 LRRC8A is essential for swelling-activated chloride current and for regulatory volume decrease in astrocytes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 47 29957062
2004 LRRC8 involved in B cell development belongs to a novel family of leucine-rich repeat proteins. FEBS letters 47 15094057
2019 More than just a pressure relief valve: physiological roles of volume-regulated LRRC8 anion channels. Biological chemistry 46 31091194
2016 LRRC8A channels support TNFα-induced superoxide production by Nox1 which is required for receptor endocytosis. Free radical biology & medicine 43 27838438
2019 The Volume-Regulated Anion Channel LRRC8/VRAC Is Dispensable for Cell Proliferation and Migration. International journal of molecular sciences 41 31151189
2017 The volume-regulated anion channel (LRRC8) in nodose neurons is sensitive to acidic pH. JCI insight 41 28289711
2020 LRRC8A is essential for hypotonicity-, but not for DAMP-induced NLRP3 inflammasome activation. eLife 40 33216713
2020 LRRC8A-dependent volume-regulated anion channels contribute to ischemia-induced brain injury and glutamatergic input to hippocampal neurons. Experimental neurology 39 32598930
2019 SWELL1 promotes cell growth and metastasis of hepatocellular carcinoma in vitro and in vivo. EBioMedicine 38 31597595
2018 Intracellular and extracellular loops of LRRC8 are essential for volume-regulated anion channel function. The Journal of general physiology 38 29853476
2017 Leucine-rich repeat containing 8A (LRRC8A)-dependent volume-regulated anion channel activity is dispensable for T-cell development and function. The Journal of allergy and clinical immunology 38 28192143
2023 Structural basis for assembly and lipid-mediated gating of LRRC8A:C volume-regulated anion channels. Nature structural & molecular biology 37 36928458
2016 Non-essential contribution of LRRC8A to volume regulation. Pflugers Archiv : European journal of physiology 36 26873248
2022 Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes. Nature communications 35 35145074
2018 GlialCAM/MLC1 modulates LRRC8/VRAC currents in an indirect manner: Implications for megalencephalic leukoencephalopathy. Neurobiology of disease 35 30076890
2018 LRRC8/VRAC anion channels are required for late stages of spermatid development in mice. The Journal of biological chemistry 34 29880644
2020 Chronic ethanol consumption and HBV induce abnormal lipid metabolism through HBx/SWELL1/arachidonic acid signaling and activate Tregs in HBV-Tg mice. Theranostics 33 32802190
2016 Specific and essential but not sufficient roles of LRRC8A in the activity of volume-sensitive outwardly rectifying anion channel (VSOR). Channels (Austin, Tex.) 33 27764579
2018 LRRC8 N termini influence pore properties and gating of volume-regulated anion channels (VRACs). The Journal of biological chemistry 32 29925591
2022 Structure of a volume-regulated heteromeric LRRC8A/C channel. Nature structural & molecular biology 31 36522427
2021 LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditions. Proceedings of the National Academy of Sciences of the United States of America 31 34083438
2021 LRRC8A influences the growth of gastric cancer cells via the p53 signaling pathway. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 30 33864161
2019 LRRC8A Expression Influences Growth of Esophageal Squamous Cell Carcinoma. The American journal of pathology 30 31323188
2021 Mechanisms of Activation of LRRC8 Volume Regulated Anion Channels. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 29 33577730
2016 Relationship between TMEM16A/anoctamin 1 and LRRC8A. Pflugers Archiv : European journal of physiology 29 27514381
2019 TTYH1 and TTYH2 Serve as LRRC8A-Independent Volume-Regulated Anion Channels in Cancer Cells. Cells 27 31181821
2019 LRRC8/VRAC channels exhibit a noncanonical permeability to glutathione, which modulates epithelial-to-mesenchymal transition (EMT). Cell death & disease 27 31804464
2018 Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice. JCI insight 27 30135305
2019 The LRRC8/VRAC anion channel facilitates myogenic differentiation of murine myoblasts by promoting membrane hyperpolarization. The Journal of biological chemistry 26 31387946
2016 Leucine-rich repeat containing protein LRRC8A is essential for swelling-activated Cl- currents and embryonic development in zebrafish. Physiological reports 26 27688432
2021 LRRC8A contributes to angiotensin II-induced cardiac hypertrophy by interacting with NADPH oxidases via the C-terminal leucine-rich repeat domain. Free radical biology & medicine 24 33515753
2019 The LRRC8 volume-regulated anion channel inhibitor, DCPIB, inhibits mitochondrial respiration independently of the channel. Physiological reports 24 31814333
2022 LRRC8A critically regulates myofibroblast phenotypes and fibrotic remodeling following myocardial infarction. Theranostics 23 35966575
2020 LRRC8A homohexameric channels poorly recapitulate VRAC regulation and pharmacology. American journal of physiology. Cell physiology 23 33356947
2021 Oxidant-resistant LRRC8A/C anion channels support superoxide production by NADPH oxidase 1. The Journal of physiology 22 33932953
2017 Induction of adipose and hepatic SWELL1 expression is required for maintaining systemic insulin-sensitivity in obesity. Channels (Austin, Tex.) 22 28873008
2024 Activation of osmo-sensitive LRRC8 anion channels in macrophages is important for micro-crystallin joint inflammation. Nature communications 20 39294178
2022 Renal Deletion of LRRC8/VRAC Channels Induces Proximal Tubulopathy. Journal of the American Society of Nephrology : JASN 20 35777784
2023 Cell volume controlled by LRRC8A-formed volume-regulated anion channels fine-tunes T cell activation and function. Nature communications 19 37925509
2022 Regulators of cell volume: The structural and functional properties of anion channels of the LRRC8 family. Current opinion in structural biology 19 35504105
2022 Structure-function relationships of the LRRC8 subunits and subdomains of the volume-regulated anion channel (VRAC). Frontiers in cellular neuroscience 19 36035259
2019 Inhibition of angiotensin II-induced cerebrovascular smooth muscle cell proliferation by LRRC8A downregulation through suppressing PI3K/AKT activation. Human cell 19 31127489
2019 CysLT1 receptor antagonists pranlukast and zafirlukast inhibit LRRC8-mediated volume regulated anion channels independently of the receptor. American journal of physiology. Cell physiology 19 31390227
2019 Absolute Protein Amounts and Relative Abundance of Volume-regulated Anion Channel (VRAC) LRRC8 Subunits in Cells and Tissues Revealed by Quantitative Immunoblotting. International journal of molecular sciences 19 31771171
2021 Regulation of Anion Channel LRRC8 Volume-Regulated Anion Channels in Transport of 2'3'-Cyclic GMP-AMP and Cisplatin under Steady State and Inflammation. Journal of immunology (Baltimore, Md. : 1950) 18 33827893
2018 Hypotonic stress response of human keratinocytes involves LRRC8A as component of volume-regulated anion channels. Experimental dermatology 18 30252954
2023 Structural insights into anion selectivity and activation mechanism of LRRC8 volume-regulated anion channels. Cell reports 17 37543949
2021 Late adolescence mortality in mice with brain-specific deletion of the volume-regulated anion channel subunit LRRC8A. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17 34469026
2016 Distinct contributions of LRRC8A and its paralogs to the VSOR anion channel from those of the ASOR anion channel. Channels (Austin, Tex.) 17 27579940
2023 LRRC8A anion channels modulate vascular reactivity via association with myosin phosphatase rho interacting protein. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16 37310356
2017 Cisplatin activates volume sensitive LRRC8 channel mediated currents in Xenopus oocytes. Channels (Austin, Tex.) 16 28121479
2023 Conditional deletion of LRRC8A in the brain reduces stroke damage independently of swelling-activated glutamate release. iScience 15 37182109
2022 LRRC8A is dispensable for a variety of microglial functions and response to acute stroke. Glia 15 35150591
2022 Inhibition of the LRRC8A channel promotes microglia/macrophage phagocytosis and improves outcomes after intracerebral hemorrhagic stroke. iScience 15 36465125
2024 Interactomic exploration of LRRC8A in volume-regulated anion channels. Cell death discovery 14 38909013
2024 The SWELL1 Channel Promotes Ischemic Brain Damage by Mediating Neuronal Swelling and Glutamate Toxicity. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 14 39056405
2022 Recent Advances in the Structural Biology of the Volume-Regulated Anion Channel LRRC8. Frontiers in pharmacology 14 35645818
2021 Volume-regulated chloride channel regulates cell proliferation and is involved in the possible interaction between TMEM16A and LRRC8A in human metastatic oral squamous cell carcinoma cells. European journal of pharmacology 14 33476655
2022 Loss of the volume-regulated anion channel components LRRC8A and LRRC8D limits platinum drug efficacy. Cancer research communications 13 36467895
2022 Activation of Swell1 in microglia suppresses neuroinflammation and reduces brain damage in ischemic stroke. Neurobiology of disease 13 36511337
2018 LRRC8A potentiates temozolomide sensitivity in glioma cells via activating mitochondria-dependent apoptotic pathway. Human cell 13 30426452
2024 LRRC8A as a central mediator promotes colon cancer metastasis by regulating PIP5K1B/PIP2 pathway. Biochimica et biophysica acta. Molecular basis of disease 12 38350542
2021 LRRC8A is essential for volume-regulated anion channel in smooth muscle cells contributing to cerebrovascular remodeling during hypertension. Cell proliferation 12 34725866
2020 Ca2+ Dependence of Volume-Regulated VRAC/LRRC8 and TMEM16A Cl- Channels. Frontiers in cell and developmental biology 12 33335902
2019 The LRRC8-mediated volume-regulated anion channel is altered in glaucoma. Scientific reports 12 30931966
2020 LRRC8 channel activation and reduction in cytosolic chloride concentration during early differentiation of C2C12 myoblasts. Biochemical and biophysical research communications 11 32892951
2018 Expression of LRRC8/VRAC Currents in Xenopus Oocytes: Advantages and Caveats. International journal of molecular sciences 11 29498698
2015 Protolichesterinic Acid, Isolated from the Lichen Cetraria islandica, Reduces LRRC8A Expression and Volume-Sensitive Release of Organic Osmolytes in Human Lung Epithelial Cancer Cells. Phytotherapy research : PTR 11 26549524
2024 ATP-elicited Cation Fluxes Promote Volume-regulated Anion Channel LRRC8/VRAC Transport cGAMP for Antitumor Immunity. Journal of immunology (Baltimore, Md. : 1950) 10 38847616