{"gene":"LRRC8C","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2004,"finding":"LRRC8C (alias AD158) was identified as a member of the LRRC8 family of leucine-rich repeat proteins with predicted structure consisting of 16 extracellular LRRs and four transmembrane regions, implicated in proliferation and activation of lymphocytes and monocytes.","method":"Homology-based sequence analysis and predicted structural characterization","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational/structural prediction only, no direct functional experiment on LRRC8C specifically","pmids":["15094057"],"is_preprint":false},{"year":2014,"finding":"LRRC8D interacts with LRRC8A, LRRC8B, and LRRC8C, as determined by co-immunoprecipitation, supporting a model where LRRC8 proteins form heteromeric complexes that mediate solute transport.","method":"Co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP showing LRRC8C interaction with LRRC8D, single lab but multiple interactors tested","pmids":["24782309"],"is_preprint":false},{"year":2015,"finding":"LRRC8C is a subunit of heteromeric volume-regulated anion channels (VRACs) but does not contribute to cisplatin/carboplatin uptake under isotonic or hypotonic conditions; loss of LRRC8C did not increase resistance to platinum-based drugs, in contrast to LRRC8A and LRRC8D.","method":"CRISPR/genetic knockout with drug uptake and cell viability assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with quantitative drug uptake assays, multiple subunits tested, replicated across conditions","pmids":["26530471"],"is_preprint":false},{"year":2016,"finding":"The C-terminal residues of the first extracellular loop (EL1) of LRRC8C, specifically equivalent residues to Lys-98 and Asp-100 in LRRC8A, are major determinants of VRAC inactivation kinetics and anion selectivity, as determined using LRRC8C/LRRC8E chimeras and point mutations.","method":"Chimeric channel construction, point mutagenesis, patch-clamp electrophysiology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with functional electrophysiology, single lab but multiple orthogonal approaches","pmids":["27325695"],"is_preprint":false},{"year":2016,"finding":"Combinatory expression of LRRC8A with LRRC8D and LRRC8C is essential for VSOR (VRAC) activity in HeLa cells, as demonstrated by double, triple, and quadruple gene-silencing studies.","method":"RNA silencing (multiple gene combinations), electrophysiology","journal":"Channels (Austin, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — combinatorial RNAi with electrophysiology, single lab","pmids":["27579940"],"is_preprint":false},{"year":2017,"finding":"In primary rat astrocytes, LRRC8A/C/E-containing (and LRRC8D-containing) heteromeric VRACs preferentially conduct charged osmolytes (d-aspartate), while LRRC8A/D-containing VRACs dominate release of uncharged osmolytes (taurine, myo-inositol); LRRC8C+LRRC8E knockdown strongly reduced charged osmolyte efflux but not uncharged osmolyte release.","method":"RNAi knockdown combined with radiotracer efflux assays","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple subunit RNAi combinations with quantitative radiotracer assays, multiple substrates tested, replicated pattern","pmids":["28833202"],"is_preprint":false},{"year":2017,"finding":"LRRC8A-LRRC8C heteromeric channels are directly inhibited by oxidation of intracellular cysteine residues (e.g., by chloramine-T or tert-butyl hydroperoxide), in contrast to LRRC8A-LRRC8E heteromers which are potentiated, demonstrating subunit-dependent oxidative modulation.","method":"Patch-clamp electrophysiology with oxidant treatment on heterologously expressed fluorescently tagged LRRC8 heteromers","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct functional assay on defined heteromers with multiple oxidants, validated in native Jurkat T cells","pmids":["28841766"],"is_preprint":false},{"year":2018,"finding":"The intracellular loop (IL) of LRRC8A connecting TM2 and TM3 and the first extracellular loop (EL1) of LRRC8C are both essential for VRAC activity; replacing EL1 of LRRC8A with that of LRRC8C generates a functional homomeric VRAC with normal volume regulation, and LRRC8A IL sequences determine anion permeability, rectification, and voltage sensitivity.","method":"Chimeric channel construction, electrophysiology, cell volume regulation assays","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — chimeric channel reconstitution with multiple functional readouts (activation, permeability, rectification), single lab but orthogonal methods","pmids":["29853476"],"is_preprint":false},{"year":2018,"finding":"MLC1 modulates VRAC currents indirectly in astrocytes; absence of MLC1 leads to changes in the phosphorylation state of the VRAC subunit LRRC8C, suggesting LRRC8C is subject to post-translational regulation via MLC1-dependent signal transduction pathways (ERK phosphorylation).","method":"Western blot (phosphorylation state), RNAi knockdown and overexpression of MLC1, electrophysiology","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — phosphorylation state changes demonstrated by Western blot in astrocytes with altered MLC1 levels, single lab","pmids":["30076890"],"is_preprint":false},{"year":2020,"finding":"LRRC8A forms heteromeric complexes with LRRC8C and/or LRRC8E to transport 2'3'-cGAMP and other cyclic dinucleotides; LRRC8A/C channels mediate cGAMP import and export driven by the electrochemical gradient, and LRRC8D inhibits cGAMP transport. Sphingosine 1-phosphate activates and DCPIB inhibits channel-mediated cGAMP transport.","method":"Genetic knockout/knockdown screens, radiotracer and STING reporter assays for cGAMP transport, pharmacological manipulation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genome-wide screen, KO, functional transport assays, pharmacology), replicated in multiple cell types","pmids":["33171122"],"is_preprint":false},{"year":2020,"finding":"LRRC8A homohexamers poorly recapitulate VRAC function; coexpression of LRRC8A and LRRC8C generates heteromeric channels with strong, voltage-independent DCPIB inhibition under normal intracellular ionic strength, more closely mimicking native VRAC pharmacology than LRRC8A alone.","method":"Electrophysiology in HCT116 Lrrc8c cells, pharmacological analysis with DCPIB, mutagenesis (R103F)","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with electrophysiology under defined conditions, functional comparison of homomers vs. heteromers","pmids":["33356947"],"is_preprint":false},{"year":2021,"finding":"LRRC8C co-immunoprecipitates with NADPH oxidase 1 (Nox1) in vascular smooth muscle cells; LRRC8C knockdown inhibits TNFα-induced superoxide production, receptor endocytosis, NF-κB activation, and proliferation, positioning LRRC8A/C channels as key supporters of Nox1 activity.","method":"siRNA knockdown, co-immunoprecipitation, functional assays (O2·- production, NF-κB, proliferation)","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus multiple functional KD readouts, single lab","pmids":["33932953"],"is_preprint":false},{"year":2021,"finding":"LRRC8A/C channels are resistant to oxidant-mediated inhibition compared to LRRC8A/D channels; the extracellular loop domains (EL1, EL2) of LRRC8C confer oxidant resistance, as substitution of 8D extracellular loops into 8C conferred stronger chloramine-T-dependent inhibition.","method":"Chimeric channel construction, patch-clamp electrophysiology with oxidant treatment","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — domain-swap chimeras with electrophysiology, mechanistic identification of extracellular loops as oxidant-resistance determinants","pmids":["33932953"],"is_preprint":false},{"year":2022,"finding":"LRRC8C is a critical component of VRAC in T cells; its deletion abolishes VRAC currents and regulatory volume decrease (RVD). LRRC8C mediates transport of 2'3'-cGAMP in T cells, leading to STING and p53 activation, which inhibits T cell proliferation, survival, and cytokine production.","method":"Genetic KO (Lrrc8c-/- mice), electrophysiology, volume regulation assays, radiotracer cGAMP transport, STING/p53 pathway analysis, in vivo immune challenge models","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — comprehensive KO study with electrophysiology, transport assays, pathway rescue, and in vivo models","pmids":["35105987"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structure of murine LRRC8A/C heteromeric channels reveals hexameric assembly with a predominant A:C ratio of 2:1 (four LRRC8A and two LRRC8C subunits). LRRC8A subunits cluster in pairs stabilizing a closed state, while LRRC8C subunits show larger flexibility and destabilize tightly packed LRRC8A subunits to enhance channel activation.","method":"Cryo-electron microscopy structure determination","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure with functional interpretation, published in high-impact journal","pmids":["36522427"],"is_preprint":false},{"year":2022,"finding":"Oxidation of the start methionine of LRRC8C, with additional contribution from the LRR domain, mediates inhibition of LRRC8A-LRRC8C heteromeric channels by oxidants, as identified by chimeric and concatemeric channel analysis.","method":"Chimeric/concatemeric channel construction, mutagenesis, patch-clamp electrophysiology with oxidant treatment","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-specific mutagenesis with functional electrophysiology identifying the oxidation target, single lab","pmids":["35861288"],"is_preprint":false},{"year":2022,"finding":"In kidney, LRRC8C is exclusively localized to vascular endothelium (not nephron epithelia), as determined by immunolocalization in mice expressing epitope-tagged LRRC8 subunits.","method":"Immunolocalization using epitope-tagged knock-in mice","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by epitope-tag knock-in, single lab, tissue-specific finding","pmids":["35777784"],"is_preprint":false},{"year":2024,"finding":"HSV-1 protein UL56 targets LRRC8A and LRRC8C for degradation (at least partially via proteasomal turnover), thereby inhibiting cGAMP uptake via VRAC channels and reducing intercellular cGAMP-mediated innate immune signaling.","method":"Viral infection assays, proteasome inhibition, protein degradation quantification, cGAMP transport functional assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic identification of viral protein causing LRRC8C degradation with functional transport readout, single lab","pmids":["38652659"],"is_preprint":false},{"year":2024,"finding":"cGAMP produced by tumor cGAS is transported via LRRC8C channels into endothelial cells, where it activates STING signaling to enhance lymphocyte recruitment and transendothelial migration, contributing to vascular normalization in liver cancer.","method":"Preclinical liver cancer models with cGAS/STING-deficient mice, in vivo functional studies","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse models with mechanistic pathway analysis, but LRRC8C-specific evidence within a complex multi-gene context","pmids":["38177099"],"is_preprint":false},{"year":2024,"finding":"De novo gain-of-function variants in LRRC8C at the pore/cytoplasmic domain boundary cause constitutive channel activation (activity even at isotonic conditions) due to increased structural flexibility of the mutant proteins, resulting in a dominant multisystem human disorder affecting blood vessels, brain, eyes, and bones.","method":"Cryo-EM structural analysis of mutant proteins, electrophysiology of co-expressed LRRC8A + mutant LRRC8C","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with functional electrophysiology demonstrating gain-of-function mechanism","pmids":["39623139"],"is_preprint":false},{"year":2025,"finding":"In endothelial cells, LRRC8C forms heteromeric complexes with LRRC8A and LRRC8B (not LRRC8D); LRRC8C depletion reduces endothelial VRAC currents, inhibits AKT-eNOS phosphorylation, increases myogenic tone, impairs eNOS-dependent vasodilation, and exacerbates angiotensin-induced hypertension in vivo.","method":"Co-immunoprecipitation with epitope-tagged knock-in mice, siRNA knockdown in HUVECs, electrophysiology, pressure myography, in vivo hypertension model","journal":"Hypertension (Dallas, Tex. : 1979)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP in vivo + multiple functional KO/KD readouts + in vivo model, multiple orthogonal methods","pmids":["41636028"],"is_preprint":false},{"year":2025,"finding":"Zafirlukast and pranlukast inhibit LRRC8A/C heteromeric channels by binding to the N-terminal domain and inter-subunit fenestrae between TM1 and TM2; mutations in NTD, TM1, and TM2 alter sensitivity to both drugs, and inhibition involves destabilization of pore-lipid interactions promoting channel inactivation.","method":"Molecular dynamics simulation, mutagenesis, patch-clamp electrophysiology with chimeric homomeric 8C-8A(IL125) and heteromeric 8A/8C channels","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in silico docking plus mutagenesis validated by electrophysiology, two structurally distinct drugs tested, mechanistic model proposed","pmids":["41053296"],"is_preprint":false},{"year":2025,"finding":"In brain astrocytes, LRRC8A and LRRC8C are key components of glutamate-permeable VRACs; LRRC8C knockdown reduces swelling-activated glutamate (D-aspartate) release by ~56%; knockdown of LRRC8A or LRRC8C reciprocally reduces the protein stability of the partner subunit without affecting mRNA levels, indicating mutual post-translational stabilization.","method":"RNAi knockdown in primary astrocytes, radiotracer efflux assays, Western blot for protein stability, qRT-PCR","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNAi, radiotracer, Western blot, qPCR) in primary cells, mechanistic insight into mutual protein stabilization","pmids":["41740631"],"is_preprint":false}],"current_model":"LRRC8C is a non-obligatory subunit of heteromeric volume-regulated anion channels (VRACs), forming hexameric complexes with the essential LRRC8A subunit (predominantly in a 4:2 LRRC8A:LRRC8C ratio as shown by cryo-EM); LRRC8C determines channel gating, inactivation kinetics, anion/substrate selectivity (including permeability to charged osmolytes, glutamate, and cyclic dinucleotides such as cGAMP), and oxidant sensitivity (via oxidation of its start methionine), and plays cell-type-specific roles including abolishing VRAC currents and RVD in T cells, supporting Nox1-dependent superoxide signaling in vascular smooth muscle, enabling AKT-eNOS signaling in endothelial cells, and facilitating STING-p53-mediated immune suppression through cGAMP transport; gain-of-function variants at the LRRC8C pore/cytoplasmic domain boundary cause constitutive channel activation and a human multisystem disorder."},"narrative":{"mechanistic_narrative":"LRRC8C is a non-obligatory, accessory subunit of heteromeric volume-regulated anion channels (VRACs), assembling with the essential LRRC8A subunit and additional LRRC8 paralogs into hexameric complexes that mediate swelling-activated anion and osmolyte transport [PMID:27579940, PMID:28833202, PMID:36522427]. Cryo-EM of murine LRRC8A/C channels shows a hexamer with a predominant 4:2 LRRC8A:LRRC8C stoichiometry, in which the more flexible LRRC8C subunits destabilize the tightly packed LRRC8A pairs to favor channel activation [PMID:36522427]. LRRC8C contributes subunit-specific functional properties: residues at the C-terminus of its first extracellular loop govern inactivation kinetics and anion selectivity [PMID:27325695, PMID:29853476], and LRRC8A/C channels display strong DCPIB sensitivity that recapitulates native VRAC pharmacology [PMID:33356947]. The channel's substrate scope extends beyond inorganic anions to charged osmolytes such as D-aspartate and glutamate [PMID:28833202, PMID:41740631] and to the cyclic dinucleotide 2'3'-cGAMP, which LRRC8A/C complexes import and export down the electrochemical gradient to drive STING signaling [PMID:33171122]. LRRC8C also confers oxidant modulation: oxidation of its start methionine, with a contribution from the LRR domain, inhibits LRRC8A/C channels, while its extracellular loops render these channels comparatively oxidant-resistant relative to LRRC8A/D [PMID:33932953, PMID:35861288]. These properties underpin distinct physiological roles—abolishing VRAC currents, regulatory volume decrease, and cGAMP-driven STING/p53-mediated immune suppression in T cells [PMID:35105987]; supporting Nox1-dependent superoxide signaling in vascular smooth muscle [PMID:33932953]; and enabling AKT-eNOS signaling and vasodilation in endothelium where LRRC8C partners with LRRC8A and LRRC8B [PMID:41636028]. De novo gain-of-function variants at the LRRC8C pore/cytoplasmic domain boundary cause constitutive channel activation and a dominant human multisystem disorder affecting blood vessels, brain, eyes, and bones [PMID:39623139].","teleology":[{"year":2004,"claim":"Before any functional assay, LRRC8C needed to be placed within a protein family and given a candidate architecture, establishing it as a leucine-rich repeat membrane protein linked to immune cell activation.","evidence":"Homology-based sequence and predicted structural analysis","pmids":["15094057"],"confidence":"Low","gaps":["Computational prediction only with no direct functional experiment","No evidence of channel activity or VRAC role at this stage","Predicted topology not experimentally validated"]},{"year":2014,"claim":"Establishing whether LRRC8 proteins act alone or in complex was needed to define the molecular unit of transport; co-IP showed LRRC8C physically associates with other LRRC8 paralogs in heteromeric assemblies.","evidence":"Co-immunoprecipitation of LRRC8C with LRRC8A/B/D","pmids":["24782309"],"confidence":"Medium","gaps":["Stoichiometry and architecture of complexes not resolved","Functional consequence of each interaction not defined"]},{"year":2015,"claim":"Resolving which subunits drive channel cargo specificity, knockout work showed LRRC8C is a VRAC subunit but, unlike LRRC8A/D, does not contribute to platinum-drug uptake, establishing subunit-specific substrate roles.","evidence":"CRISPR knockout with drug uptake and viability assays","pmids":["26530471"],"confidence":"High","gaps":["Which substrates LRRC8C does favor was not yet defined","Did not address electrophysiological contribution"]},{"year":2016,"claim":"To map which protein regions set channel behavior, chimera and mutagenesis studies localized inactivation kinetics and anion selectivity to the C-terminus of the LRRC8C first extracellular loop, and showed EL1 is essential for VRAC activity.","evidence":"LRRC8C/E chimeras, point mutagenesis, patch-clamp; combinatorial RNAi electrophysiology","pmids":["27325695","27579940","29853476"],"confidence":"High","gaps":["Atomic structure of the gating element not yet available","Contribution of cytoplasmic domains incompletely defined"]},{"year":2017,"claim":"Defining the physiological cargo, subunit-resolved knockdown and oxidant assays showed LRRC8C-containing channels preferentially conduct charged osmolytes and are inhibited by intracellular oxidation, distinguishing them from other heteromers.","evidence":"RNAi knockdown with radiotracer efflux assays; patch-clamp with oxidants on defined heteromers","pmids":["28833202","28841766"],"confidence":"High","gaps":["Molecular identity of the oxidation target not yet pinpointed","Whether substrate preference holds across cell types untested at this point"]},{"year":2018,"claim":"Identifying upstream regulation, MLC1 was shown to alter the phosphorylation state of LRRC8C in astrocytes, indicating LRRC8C is subject to post-translational control via ERK signaling.","evidence":"Western blot phosphorylation analysis with MLC1 manipulation and electrophysiology","pmids":["30076890"],"confidence":"Medium","gaps":["Phosphorylation sites on LRRC8C not mapped","Direct functional consequence of phosphorylation on channel gating not established"]},{"year":2020,"claim":"Extending VRAC cargo to signaling molecules, screens and transport assays established LRRC8A/C channels as bidirectional conduits for 2'3'-cGAMP and other cyclic dinucleotides, linking the channel to STING-based immune signaling; pharmacology confirmed LRRC8A/C channels mimic native VRAC.","evidence":"Genome-wide screens, radiotracer/STING reporter transport assays, pharmacology; DCPIB electrophysiology with R103F mutagenesis","pmids":["33171122","33356947"],"confidence":"High","gaps":["Directionality control and regulation in vivo not fully defined","Whether cGAMP transport competes with osmolyte conduction unresolved"]},{"year":2021,"claim":"Connecting the channel to vascular redox signaling, LRRC8C was shown to co-IP with Nox1 and to support TNFα-induced superoxide production and proliferation in smooth muscle, while domain swaps localized oxidant resistance to LRRC8C extracellular loops.","evidence":"siRNA knockdown, reciprocal co-IP, functional assays; chimeric channel electrophysiology with oxidants","pmids":["33932953"],"confidence":"High","gaps":["Stoichiometry of LRRC8C-Nox1 interaction unknown","Whether interaction is direct not established"]},{"year":2022,"claim":"A convergence of structure, genetics, and cell biology defined the channel's architecture and a major physiological role: cryo-EM revealed a 4:2 LRRC8A:LRRC8C hexamer with LRRC8C promoting activation; the oxidation site was mapped to the LRRC8C start methionine; and T cell knockout linked LRRC8C-mediated cGAMP transport to STING-p53 immune suppression.","evidence":"Cryo-EM; chimeric/concatemeric mutagenesis electrophysiology; Lrrc8c-/- mice with electrophysiology, transport assays, and in vivo immune models; epitope-tag knock-in immunolocalization","pmids":["36522427","35861288","35105987","35777784"],"confidence":"High","gaps":["Gating transition between closed and open states not fully captured","Tissue distribution beyond kidney endothelium and T cells incompletely mapped"]},{"year":2024,"claim":"Disease relevance and physiological regulation were established: de novo gain-of-function variants at the pore/cytoplasmic boundary cause constitutive activation and a human multisystem disorder, while HSV-1 UL56 degrades LRRC8C to block cGAMP uptake and tumor-derived cGAMP enters endothelium via LRRC8C to drive STING-mediated vascular normalization.","evidence":"Cryo-EM and electrophysiology of mutants; viral infection and proteasome assays; preclinical liver cancer cGAS/STING mouse models","pmids":["39623139","38652659","38177099"],"confidence":"High","gaps":["Genotype-phenotype correlation across affected organs not detailed","Whether other viral or endogenous regulators target LRRC8C unknown"]},{"year":2025,"claim":"Cell-type-specific assembly and pharmacology were refined: in endothelium LRRC8C partners with LRRC8A and LRRC8B to sustain AKT-eNOS-dependent vasodilation; LRRC8A/C channels are inhibited by leukotriene-receptor antagonists binding the N-terminal/fenestrae region; and LRRC8A and LRRC8C mutually stabilize each other post-translationally in glutamate-permeable astrocytic VRACs.","evidence":"Co-IP in knock-in mice, siRNA in HUVECs, pressure myography, in vivo hypertension model; MD simulation and mutagenesis electrophysiology; RNAi with radiotracer efflux and Western blot in astrocytes","pmids":["41636028","41053296","41740631"],"confidence":"High","gaps":["Mechanism coupling AKT-eNOS to VRAC activity not fully resolved","How partner subunit identity is selected per tissue unknown"]},{"year":null,"claim":"How LRRC8C dynamically switches between conducting inorganic anions, charged osmolytes, and immune second messengers, and how its assembly partner choice is determined across tissues, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No open-state structure capturing substrate translocation","Rules governing tissue-specific LRRC8 paralog pairing unknown","Physiological signals that gate cGAMP versus osmolyte permeation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[4,5,9,13]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[15,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[14,16]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[5,9,22]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,13,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,20]}],"complexes":["VRAC (volume-regulated anion channel)"],"partners":["LRRC8A","LRRC8B","LRRC8D","NOX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TDW0","full_name":"Volume-regulated anion channel subunit LRRC8C","aliases":["Factor for adipocyte differentiation 158","Leucine-rich repeat-containing protein 8C"],"length_aa":803,"mass_kda":92.5,"function":"Non-essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes (PubMed:24790029, PubMed:26824658, PubMed:28193731, PubMed:36897307, PubMed:39623139). The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine (PubMed:24790029, PubMed:26824658, PubMed:28193731). Plays a redundant role in the efflux of amino acids, such as aspartate and glutamate, in response to osmotic stress (PubMed:24790029, PubMed:26824658, PubMed:28193731). The VRAC channel also mediates transport of immunoreactive cyclic dinucleotide GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol (PubMed:33171122). Channel activity requires LRRC8A plus at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition (PubMed:24790029, PubMed:26824658, PubMed:28193731)","subcellular_location":"Cell membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q8TDW0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LRRC8C","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SCAMP2","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2},{"gene":"NCLN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LRRC8C","total_profiled":1310},"omim":[{"mim_id":"621056","title":"TELANGIECTASIA, IMPAIRED INTELLECTUAL DEVELOPMENT, MICROCEPHALY, METAPHYSEAL DYSPLASIA, EYE ABNORMALITIES, AND SHORT STATURE; TIMES","url":"https://www.omim.org/entry/621056"},{"mim_id":"612889","title":"LEUCINE-RICH REPEAT-CONTAINING PROTEIN 8C; LRRC8C","url":"https://www.omim.org/entry/612889"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Golgi apparatus","reliability":"Uncertain"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LRRC8C"},"hgnc":{"alias_symbol":["AD158"],"prev_symbol":[]},"alphafold":{"accession":"Q8TDW0","domains":[{"cath_id":"1.20.1440.80","chopping":"5-58_105-148_263-357","consensus_level":"medium","plddt":88.2062,"start":5,"end":357},{"cath_id":"3.80.10.10","chopping":"414-526_534-545","consensus_level":"medium","plddt":87.5684,"start":414,"end":545},{"cath_id":"3.80.10.10","chopping":"625-803","consensus_level":"medium","plddt":93.1774,"start":625,"end":803}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TDW0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TDW0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TDW0-F1-predicted_aligned_error_v6.png","plddt_mean":83.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LRRC8C","jax_strain_url":"https://www.jax.org/strain/search?query=LRRC8C"},"sequence":{"accession":"Q8TDW0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TDW0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TDW0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TDW0"}},"corpus_meta":[{"pmid":"26530471","id":"PMC_26530471","title":"Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs.","date":"2015","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/26530471","citation_count":225,"is_preprint":false},{"pmid":"33171122","id":"PMC_33171122","title":"LRRC8A:C/E Heteromeric Channels Are Ubiquitous Transporters of cGAMP.","date":"2020","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/33171122","citation_count":155,"is_preprint":false},{"pmid":"35105987","id":"PMC_35105987","title":"The volume-regulated anion channel LRRC8C suppresses T cell function by regulating cyclic dinucleotide transport and STING-p53 signaling.","date":"2022","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35105987","citation_count":98,"is_preprint":false},{"pmid":"28833202","id":"PMC_28833202","title":"Molecular composition and heterogeneity of the LRRC8-containing swelling-activated osmolyte channels in primary rat 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loss of LRRC8C did not increase resistance to platinum-based drugs, in contrast to LRRC8A and LRRC8D.\",\n      \"method\": \"CRISPR/genetic knockout with drug uptake and cell viability assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with quantitative drug uptake assays, multiple subunits tested, replicated across conditions\",\n      \"pmids\": [\"26530471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The C-terminal residues of the first extracellular loop (EL1) of LRRC8C, specifically equivalent residues to Lys-98 and Asp-100 in LRRC8A, are major determinants of VRAC inactivation kinetics and anion selectivity, as determined using LRRC8C/LRRC8E chimeras and point mutations.\",\n      \"method\": \"Chimeric channel construction, point mutagenesis, patch-clamp electrophysiology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with functional electrophysiology, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"27325695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Combinatory expression of LRRC8A with LRRC8D and LRRC8C is essential for VSOR (VRAC) activity in HeLa cells, as demonstrated by double, triple, and quadruple gene-silencing studies.\",\n      \"method\": \"RNA silencing (multiple gene combinations), electrophysiology\",\n      \"journal\": \"Channels (Austin, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — combinatorial RNAi with electrophysiology, single lab\",\n      \"pmids\": [\"27579940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In primary rat astrocytes, LRRC8A/C/E-containing (and LRRC8D-containing) heteromeric VRACs preferentially conduct charged osmolytes (d-aspartate), while LRRC8A/D-containing VRACs dominate release of uncharged osmolytes (taurine, myo-inositol); LRRC8C+LRRC8E knockdown strongly reduced charged osmolyte efflux but not uncharged osmolyte release.\",\n      \"method\": \"RNAi knockdown combined with radiotracer efflux assays\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple subunit RNAi combinations with quantitative radiotracer assays, multiple substrates tested, replicated pattern\",\n      \"pmids\": [\"28833202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LRRC8A-LRRC8C heteromeric channels are directly inhibited by oxidation of intracellular cysteine residues (e.g., by chloramine-T or tert-butyl hydroperoxide), in contrast to LRRC8A-LRRC8E heteromers which are potentiated, demonstrating subunit-dependent oxidative modulation.\",\n      \"method\": \"Patch-clamp electrophysiology with oxidant treatment on heterologously expressed fluorescently tagged LRRC8 heteromers\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct functional assay on defined heteromers with multiple oxidants, validated in native Jurkat T cells\",\n      \"pmids\": [\"28841766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The intracellular loop (IL) of LRRC8A connecting TM2 and TM3 and the first extracellular loop (EL1) of LRRC8C are both essential for VRAC activity; replacing EL1 of LRRC8A with that of LRRC8C generates a functional homomeric VRAC with normal volume regulation, and LRRC8A IL sequences determine anion permeability, rectification, and voltage sensitivity.\",\n      \"method\": \"Chimeric channel construction, electrophysiology, cell volume regulation assays\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — chimeric channel reconstitution with multiple functional readouts (activation, permeability, rectification), single lab but orthogonal methods\",\n      \"pmids\": [\"29853476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MLC1 modulates VRAC currents indirectly in astrocytes; absence of MLC1 leads to changes in the phosphorylation state of the VRAC subunit LRRC8C, suggesting LRRC8C is subject to post-translational regulation via MLC1-dependent signal transduction pathways (ERK phosphorylation).\",\n      \"method\": \"Western blot (phosphorylation state), RNAi knockdown and overexpression of MLC1, electrophysiology\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — phosphorylation state changes demonstrated by Western blot in astrocytes with altered MLC1 levels, single lab\",\n      \"pmids\": [\"30076890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LRRC8A forms heteromeric complexes with LRRC8C and/or LRRC8E to transport 2'3'-cGAMP and other cyclic dinucleotides; LRRC8A/C channels mediate cGAMP import and export driven by the electrochemical gradient, and LRRC8D inhibits cGAMP transport. Sphingosine 1-phosphate activates and DCPIB inhibits channel-mediated cGAMP transport.\",\n      \"method\": \"Genetic knockout/knockdown screens, radiotracer and STING reporter assays for cGAMP transport, pharmacological manipulation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genome-wide screen, KO, functional transport assays, pharmacology), replicated in multiple cell types\",\n      \"pmids\": [\"33171122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LRRC8A homohexamers poorly recapitulate VRAC function; coexpression of LRRC8A and LRRC8C generates heteromeric channels with strong, voltage-independent DCPIB inhibition under normal intracellular ionic strength, more closely mimicking native VRAC pharmacology than LRRC8A alone.\",\n      \"method\": \"Electrophysiology in HCT116 Lrrc8c cells, pharmacological analysis with DCPIB, mutagenesis (R103F)\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with electrophysiology under defined conditions, functional comparison of homomers vs. heteromers\",\n      \"pmids\": [\"33356947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LRRC8C co-immunoprecipitates with NADPH oxidase 1 (Nox1) in vascular smooth muscle cells; LRRC8C knockdown inhibits TNFα-induced superoxide production, receptor endocytosis, NF-κB activation, and proliferation, positioning LRRC8A/C channels as key supporters of Nox1 activity.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, functional assays (O2·- production, NF-κB, proliferation)\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus multiple functional KD readouts, single lab\",\n      \"pmids\": [\"33932953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LRRC8A/C channels are resistant to oxidant-mediated inhibition compared to LRRC8A/D channels; the extracellular loop domains (EL1, EL2) of LRRC8C confer oxidant resistance, as substitution of 8D extracellular loops into 8C conferred stronger chloramine-T-dependent inhibition.\",\n      \"method\": \"Chimeric channel construction, patch-clamp electrophysiology with oxidant treatment\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — domain-swap chimeras with electrophysiology, mechanistic identification of extracellular loops as oxidant-resistance determinants\",\n      \"pmids\": [\"33932953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LRRC8C is a critical component of VRAC in T cells; its deletion abolishes VRAC currents and regulatory volume decrease (RVD). LRRC8C mediates transport of 2'3'-cGAMP in T cells, leading to STING and p53 activation, which inhibits T cell proliferation, survival, and cytokine production.\",\n      \"method\": \"Genetic KO (Lrrc8c-/- mice), electrophysiology, volume regulation assays, radiotracer cGAMP transport, STING/p53 pathway analysis, in vivo immune challenge models\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — comprehensive KO study with electrophysiology, transport assays, pathway rescue, and in vivo models\",\n      \"pmids\": [\"35105987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structure of murine LRRC8A/C heteromeric channels reveals hexameric assembly with a predominant A:C ratio of 2:1 (four LRRC8A and two LRRC8C subunits). LRRC8A subunits cluster in pairs stabilizing a closed state, while LRRC8C subunits show larger flexibility and destabilize tightly packed LRRC8A subunits to enhance channel activation.\",\n      \"method\": \"Cryo-electron microscopy structure determination\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure with functional interpretation, published in high-impact journal\",\n      \"pmids\": [\"36522427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Oxidation of the start methionine of LRRC8C, with additional contribution from the LRR domain, mediates inhibition of LRRC8A-LRRC8C heteromeric channels by oxidants, as identified by chimeric and concatemeric channel analysis.\",\n      \"method\": \"Chimeric/concatemeric channel construction, mutagenesis, patch-clamp electrophysiology with oxidant treatment\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-specific mutagenesis with functional electrophysiology identifying the oxidation target, single lab\",\n      \"pmids\": [\"35861288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In kidney, LRRC8C is exclusively localized to vascular endothelium (not nephron epithelia), as determined by immunolocalization in mice expressing epitope-tagged LRRC8 subunits.\",\n      \"method\": \"Immunolocalization using epitope-tagged knock-in mice\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by epitope-tag knock-in, single lab, tissue-specific finding\",\n      \"pmids\": [\"35777784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HSV-1 protein UL56 targets LRRC8A and LRRC8C for degradation (at least partially via proteasomal turnover), thereby inhibiting cGAMP uptake via VRAC channels and reducing intercellular cGAMP-mediated innate immune signaling.\",\n      \"method\": \"Viral infection assays, proteasome inhibition, protein degradation quantification, cGAMP transport functional assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic identification of viral protein causing LRRC8C degradation with functional transport readout, single lab\",\n      \"pmids\": [\"38652659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"cGAMP produced by tumor cGAS is transported via LRRC8C channels into endothelial cells, where it activates STING signaling to enhance lymphocyte recruitment and transendothelial migration, contributing to vascular normalization in liver cancer.\",\n      \"method\": \"Preclinical liver cancer models with cGAS/STING-deficient mice, in vivo functional studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse models with mechanistic pathway analysis, but LRRC8C-specific evidence within a complex multi-gene context\",\n      \"pmids\": [\"38177099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"De novo gain-of-function variants in LRRC8C at the pore/cytoplasmic domain boundary cause constitutive channel activation (activity even at isotonic conditions) due to increased structural flexibility of the mutant proteins, resulting in a dominant multisystem human disorder affecting blood vessels, brain, eyes, and bones.\",\n      \"method\": \"Cryo-EM structural analysis of mutant proteins, electrophysiology of co-expressed LRRC8A + mutant LRRC8C\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with functional electrophysiology demonstrating gain-of-function mechanism\",\n      \"pmids\": [\"39623139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In endothelial cells, LRRC8C forms heteromeric complexes with LRRC8A and LRRC8B (not LRRC8D); LRRC8C depletion reduces endothelial VRAC currents, inhibits AKT-eNOS phosphorylation, increases myogenic tone, impairs eNOS-dependent vasodilation, and exacerbates angiotensin-induced hypertension in vivo.\",\n      \"method\": \"Co-immunoprecipitation with epitope-tagged knock-in mice, siRNA knockdown in HUVECs, electrophysiology, pressure myography, in vivo hypertension model\",\n      \"journal\": \"Hypertension (Dallas, Tex. : 1979)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP in vivo + multiple functional KO/KD readouts + in vivo model, multiple orthogonal methods\",\n      \"pmids\": [\"41636028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Zafirlukast and pranlukast inhibit LRRC8A/C heteromeric channels by binding to the N-terminal domain and inter-subunit fenestrae between TM1 and TM2; mutations in NTD, TM1, and TM2 alter sensitivity to both drugs, and inhibition involves destabilization of pore-lipid interactions promoting channel inactivation.\",\n      \"method\": \"Molecular dynamics simulation, mutagenesis, patch-clamp electrophysiology with chimeric homomeric 8C-8A(IL125) and heteromeric 8A/8C channels\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in silico docking plus mutagenesis validated by electrophysiology, two structurally distinct drugs tested, mechanistic model proposed\",\n      \"pmids\": [\"41053296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In brain astrocytes, LRRC8A and LRRC8C are key components of glutamate-permeable VRACs; LRRC8C knockdown reduces swelling-activated glutamate (D-aspartate) release by ~56%; knockdown of LRRC8A or LRRC8C reciprocally reduces the protein stability of the partner subunit without affecting mRNA levels, indicating mutual post-translational stabilization.\",\n      \"method\": \"RNAi knockdown in primary astrocytes, radiotracer efflux assays, Western blot for protein stability, qRT-PCR\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNAi, radiotracer, Western blot, qPCR) in primary cells, mechanistic insight into mutual protein stabilization\",\n      \"pmids\": [\"41740631\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LRRC8C is a non-obligatory subunit of heteromeric volume-regulated anion channels (VRACs), forming hexameric complexes with the essential LRRC8A subunit (predominantly in a 4:2 LRRC8A:LRRC8C ratio as shown by cryo-EM); LRRC8C determines channel gating, inactivation kinetics, anion/substrate selectivity (including permeability to charged osmolytes, glutamate, and cyclic dinucleotides such as cGAMP), and oxidant sensitivity (via oxidation of its start methionine), and plays cell-type-specific roles including abolishing VRAC currents and RVD in T cells, supporting Nox1-dependent superoxide signaling in vascular smooth muscle, enabling AKT-eNOS signaling in endothelial cells, and facilitating STING-p53-mediated immune suppression through cGAMP transport; gain-of-function variants at the LRRC8C pore/cytoplasmic domain boundary cause constitutive channel activation and a human multisystem disorder.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LRRC8C is a non-obligatory, accessory subunit of heteromeric volume-regulated anion channels (VRACs), assembling with the essential LRRC8A subunit and additional LRRC8 paralogs into hexameric complexes that mediate swelling-activated anion and osmolyte transport [#4, #5, #14]. Cryo-EM of murine LRRC8A/C channels shows a hexamer with a predominant 4:2 LRRC8A:LRRC8C stoichiometry, in which the more flexible LRRC8C subunits destabilize the tightly packed LRRC8A pairs to favor channel activation [#14]. LRRC8C contributes subunit-specific functional properties: residues at the C-terminus of its first extracellular loop govern inactivation kinetics and anion selectivity [#3, #7], and LRRC8A/C channels display strong DCPIB sensitivity that recapitulates native VRAC pharmacology [#10]. The channel's substrate scope extends beyond inorganic anions to charged osmolytes such as D-aspartate and glutamate [#5, #22] and to the cyclic dinucleotide 2'3'-cGAMP, which LRRC8A/C complexes import and export down the electrochemical gradient to drive STING signaling [#9]. LRRC8C also confers oxidant modulation: oxidation of its start methionine, with a contribution from the LRR domain, inhibits LRRC8A/C channels, while its extracellular loops render these channels comparatively oxidant-resistant relative to LRRC8A/D [#12, #15]. These properties underpin distinct physiological roles—abolishing VRAC currents, regulatory volume decrease, and cGAMP-driven STING/p53-mediated immune suppression in T cells [#13]; supporting Nox1-dependent superoxide signaling in vascular smooth muscle [#11]; and enabling AKT-eNOS signaling and vasodilation in endothelium where LRRC8C partners with LRRC8A and LRRC8B [#20]. De novo gain-of-function variants at the LRRC8C pore/cytoplasmic domain boundary cause constitutive channel activation and a dominant human multisystem disorder affecting blood vessels, brain, eyes, and bones [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Before any functional assay, LRRC8C needed to be placed within a protein family and given a candidate architecture, establishing it as a leucine-rich repeat membrane protein linked to immune cell activation.\",\n      \"evidence\": \"Homology-based sequence and predicted structural analysis\",\n      \"pmids\": [\"15094057\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational prediction only with no direct functional experiment\", \"No evidence of channel activity or VRAC role at this stage\", \"Predicted topology not experimentally validated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing whether LRRC8 proteins act alone or in complex was needed to define the molecular unit of transport; co-IP showed LRRC8C physically associates with other LRRC8 paralogs in heteromeric assemblies.\",\n      \"evidence\": \"Co-immunoprecipitation of LRRC8C with LRRC8A/B/D\",\n      \"pmids\": [\"24782309\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and architecture of complexes not resolved\", \"Functional consequence of each interaction not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolving which subunits drive channel cargo specificity, knockout work showed LRRC8C is a VRAC subunit but, unlike LRRC8A/D, does not contribute to platinum-drug uptake, establishing subunit-specific substrate roles.\",\n      \"evidence\": \"CRISPR knockout with drug uptake and viability assays\",\n      \"pmids\": [\"26530471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which substrates LRRC8C does favor was not yet defined\", \"Did not address electrophysiological contribution\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"To map which protein regions set channel behavior, chimera and mutagenesis studies localized inactivation kinetics and anion selectivity to the C-terminus of the LRRC8C first extracellular loop, and showed EL1 is essential for VRAC activity.\",\n      \"evidence\": \"LRRC8C/E chimeras, point mutagenesis, patch-clamp; combinatorial RNAi electrophysiology\",\n      \"pmids\": [\"27325695\", \"27579940\", \"29853476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the gating element not yet available\", \"Contribution of cytoplasmic domains incompletely defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining the physiological cargo, subunit-resolved knockdown and oxidant assays showed LRRC8C-containing channels preferentially conduct charged osmolytes and are inhibited by intracellular oxidation, distinguishing them from other heteromers.\",\n      \"evidence\": \"RNAi knockdown with radiotracer efflux assays; patch-clamp with oxidants on defined heteromers\",\n      \"pmids\": [\"28833202\", \"28841766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of the oxidation target not yet pinpointed\", \"Whether substrate preference holds across cell types untested at this point\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying upstream regulation, MLC1 was shown to alter the phosphorylation state of LRRC8C in astrocytes, indicating LRRC8C is subject to post-translational control via ERK signaling.\",\n      \"evidence\": \"Western blot phosphorylation analysis with MLC1 manipulation and electrophysiology\",\n      \"pmids\": [\"30076890\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphorylation sites on LRRC8C not mapped\", \"Direct functional consequence of phosphorylation on channel gating not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extending VRAC cargo to signaling molecules, screens and transport assays established LRRC8A/C channels as bidirectional conduits for 2'3'-cGAMP and other cyclic dinucleotides, linking the channel to STING-based immune signaling; pharmacology confirmed LRRC8A/C channels mimic native VRAC.\",\n      \"evidence\": \"Genome-wide screens, radiotracer/STING reporter transport assays, pharmacology; DCPIB electrophysiology with R103F mutagenesis\",\n      \"pmids\": [\"33171122\", \"33356947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Directionality control and regulation in vivo not fully defined\", \"Whether cGAMP transport competes with osmolyte conduction unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connecting the channel to vascular redox signaling, LRRC8C was shown to co-IP with Nox1 and to support TNFα-induced superoxide production and proliferation in smooth muscle, while domain swaps localized oxidant resistance to LRRC8C extracellular loops.\",\n      \"evidence\": \"siRNA knockdown, reciprocal co-IP, functional assays; chimeric channel electrophysiology with oxidants\",\n      \"pmids\": [\"33932953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of LRRC8C-Nox1 interaction unknown\", \"Whether interaction is direct not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A convergence of structure, genetics, and cell biology defined the channel's architecture and a major physiological role: cryo-EM revealed a 4:2 LRRC8A:LRRC8C hexamer with LRRC8C promoting activation; the oxidation site was mapped to the LRRC8C start methionine; and T cell knockout linked LRRC8C-mediated cGAMP transport to STING-p53 immune suppression.\",\n      \"evidence\": \"Cryo-EM; chimeric/concatemeric mutagenesis electrophysiology; Lrrc8c-/- mice with electrophysiology, transport assays, and in vivo immune models; epitope-tag knock-in immunolocalization\",\n      \"pmids\": [\"36522427\", \"35861288\", \"35105987\", \"35777784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Gating transition between closed and open states not fully captured\", \"Tissue distribution beyond kidney endothelium and T cells incompletely mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Disease relevance and physiological regulation were established: de novo gain-of-function variants at the pore/cytoplasmic boundary cause constitutive activation and a human multisystem disorder, while HSV-1 UL56 degrades LRRC8C to block cGAMP uptake and tumor-derived cGAMP enters endothelium via LRRC8C to drive STING-mediated vascular normalization.\",\n      \"evidence\": \"Cryo-EM and electrophysiology of mutants; viral infection and proteasome assays; preclinical liver cancer cGAS/STING mouse models\",\n      \"pmids\": [\"39623139\", \"38652659\", \"38177099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype correlation across affected organs not detailed\", \"Whether other viral or endogenous regulators target LRRC8C unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cell-type-specific assembly and pharmacology were refined: in endothelium LRRC8C partners with LRRC8A and LRRC8B to sustain AKT-eNOS-dependent vasodilation; LRRC8A/C channels are inhibited by leukotriene-receptor antagonists binding the N-terminal/fenestrae region; and LRRC8A and LRRC8C mutually stabilize each other post-translationally in glutamate-permeable astrocytic VRACs.\",\n      \"evidence\": \"Co-IP in knock-in mice, siRNA in HUVECs, pressure myography, in vivo hypertension model; MD simulation and mutagenesis electrophysiology; RNAi with radiotracer efflux and Western blot in astrocytes\",\n      \"pmids\": [\"41636028\", \"41053296\", \"41740631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling AKT-eNOS to VRAC activity not fully resolved\", \"How partner subunit identity is selected per tissue unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LRRC8C dynamically switches between conducting inorganic anions, charged osmolytes, and immune second messengers, and how its assembly partner choice is determined across tissues, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No open-state structure capturing substrate translocation\", \"Rules governing tissue-specific LRRC8 paralog pairing unknown\", \"Physiological signals that gate cGAMP versus osmolyte permeation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [4, 5, 9, 13]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [15, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [14, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [5, 9, 22]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 13, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 20]}\n    ],\n    \"complexes\": [\"VRAC (volume-regulated anion channel)\"],\n    \"partners\": [\"LRRC8A\", \"LRRC8B\", \"LRRC8D\", \"NOX1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}