{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q8IWT6","secondaryAccessions":["Q6UXM2","Q8NCI0","Q9P2B1"],"uniProtkbId":"LRC8A_HUMAN","entryAudit":{"firstPublicDate":"2003-10-03","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2003-03-01","entryVersion":199,"sequenceVersion":1},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"36897307"}],"value":"Volume-regulated anion channel subunit LRRC8A"}},"alternativeNames":[{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"22532330"}],"value":"Leucine-rich repeat-containing protein 8A"},"shortNames":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"30127360"}],"value":"HsLRRC8A"}]},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"24725410"}],"value":"Swelling protein 1"}}]},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"22532330"},{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:19027"}],"value":"LRRC8A"},"synonyms":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"10718198"}],"value":"KIAA1437"},{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"14660746"}],"value":"LRRC8"},{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"24725410"}],"value":"SWELL1"}],"orfNames":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"12975309"}],"value":"UNQ221/PRO247"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q80WG5"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"14660746"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24725410"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24790029"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26530471"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26824658"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28193731"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29371604"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29769723"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30095067"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31270356"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33139539"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33171122"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"39909992"}],"value":"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:24725410, PubMed:24790029, PubMed:26530471, PubMed:26824658, PubMed:28193731, PubMed:29769723). The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine (PubMed:24725410, PubMed:24790029, PubMed:26530471, PubMed:26824658, PubMed:28193731, PubMed:30095067). Mediates efflux of amino acids, such as aspartate and glutamate, in response to osmotic stress (PubMed:28193731). LRRC8A and LRRC8D are required for the uptake of the drug cisplatin (PubMed:26530471). In complex with LRRC8C or LRRC8E, acts as a transporter of immunoreactive cyclic dinucleotide GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol: mediates both import and export of 2'-3'-cGAMP, thereby promoting transfer of 2'-3'-cGAMP to bystander cells (PubMed:33171122). In contrast, complexes containing LRRC8D inhibit transport of 2'-3'-cGAMP (PubMed:33171122). Required for in vivo channel activity, together with 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). Can form functional channels by itself (in vitro) (PubMed:26824658). Involved in B-cell development: required for the pro-B cell to pre-B cell transition (PubMed:14660746). Also required for T-cell development (By similarity). Required for myoblast differentiation: VRAC activity promotes membrane hyperpolarization and regulates insulin-stimulated glucose metabolism and oxygen consumption (By similarity). Also acts as a regulator of glucose-sensing in pancreatic beta cells: VRAC currents, generated in response to hypotonicity- or glucose-induced beta cell swelling, depolarize cells, thereby causing electrical excitation, leading to increase glucose sensitivity and insulin secretion (PubMed:29371604). Also plays a role in lysosome homeostasis by forming functional lysosomal VRAC channels in response to low cytoplasmic ionic strength condition: lysosomal VRAC channels are necessary for the formation of large lysosome-derived vacuoles, which store and then expel excess water to maintain cytosolic water homeostasis (PubMed:31270356, PubMed:33139539). Acts as a key factor in NLRP3 inflammasome activation by modulating itaconate efflux and mitochondria function (PubMed:39909992)"}],"commentType":"FUNCTION"},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"chloride(in) = chloride(out)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:29823"},{"database":"ChEBI","id":"CHEBI:17996"}],"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24725410"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24790029"}]}},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"iodide(out) = iodide(in)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:66324"},{"database":"ChEBI","id":"CHEBI:16382"}],"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24725410"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24790029"}]}},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"taurine(out) = taurine(in)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:66328"},{"database":"ChEBI","id":"CHEBI:507393"}],"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24790029"}]}},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"L-aspartate(out) = L-aspartate(in)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:66332"},{"database":"ChEBI","id":"CHEBI:29991"}],"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q4V8I7"}]}},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"L-glutamate(out) = L-glutamate(in)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:66336"},{"database":"ChEBI","id":"CHEBI:29985"}],"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"28193731"}]}},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"myo-inositol(out) = myo-inositol(in)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:32867"},{"database":"ChEBI","id":"CHEBI:17268"}],"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q4V8I7"}]}},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"2',3'-cGAMP(out) = 2',3'-cGAMP(in)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:66320"},{"database":"ChEBI","id":"CHEBI:143093"}],"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33171122"}]},"physiologicalReactions":[{"directionType":"left-to-right","reactionCrossReference":{"database":"Rhea","id":"RHEA:66321"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33171122"}]},{"directionType":"right-to-left","reactionCrossReference":{"database":"Rhea","id":"RHEA:66322"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33171122"}]}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q80WG5"}],"value":"Inhibited by (4-[(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]butanoic acid), which plugs the channel like a cork in a bottle by binding in the extracellular selectivity filter and sterically occluding ion conduction (By similarity). Lipids may block conduction in closed heterohexameric channels (By similarity)"}],"commentType":"ACTIVITY REGULATION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q80WG5"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24782309"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24790029"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26824658"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28193731"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30095067"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30127360"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"39909992"},{"evidenceCode":"ECO:0000305"}],"value":"Heterohexamer; oligomerizes with other LRRC8 proteins (LRRC8B, LRRC8C, LRRC8D and/or LRRC8E) to form a heterohexamer (PubMed:24782309, PubMed:24790029, PubMed:26824658, PubMed:28193731, PubMed:30095067, PubMed:30127360). Can form homohexamers in vitro, but these have lower conductance than heterohexamers (PubMed:26824658). In vivo, the subunit composition may depend primarily on expression levels, and heterooligomeric channels containing various proportions of the different LRRC8 proteins may coexist (By similarity). Interact with GRB2 (By similarity). Interacts with NOX4; this interaction prevents the ubiquitin-mediated degradation of LRRC8A (PubMed:39909992)"}],"commentType":"SUBUNIT"},{"commentType":"INTERACTION","interactions":[{"interactantOne":{"uniProtKBAccession":"Q8IWT6","intActId":"EBI-10970086"},"interactantTwo":{"uniProtKBAccession":"Q8IWT6","geneName":"LRRC8A","intActId":"EBI-10970086"},"numberOfExperiments":4,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q8IWT6","intActId":"EBI-10970086"},"interactantTwo":{"uniProtKBAccession":"Q6P9F7","geneName":"LRRC8B","intActId":"EBI-9477617"},"numberOfExperiments":5,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q8IWT6","intActId":"EBI-10970086"},"interactantTwo":{"uniProtKBAccession":"Q8TDW0","geneName":"LRRC8C","intActId":"EBI-6916516"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q8IWT6","intActId":"EBI-10970086"},"interactantTwo":{"uniProtKBAccession":"Q7L1W4","geneName":"LRRC8D","intActId":"EBI-861997"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q8IWT6","intActId":"EBI-10970086"},"interactantTwo":{"uniProtKBAccession":"Q6NSJ5","geneName":"LRRC8E","intActId":"EBI-8647013"},"numberOfExperiments":3,"organismDiffer":false}]},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33139539"}],"value":"Mainly localizes to the cell membrane, with some intracellular localization to lysosomes"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24725410"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24782309"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24790029"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26824658"},{"evidenceCode":"ECO:0000305","source":"PubMed","id":"29769723"}],"value":"Cell membrane","id":"SL-0039"},"topology":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24725410"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24782309"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24790029"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30095067"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30127360"}],"value":"Multi-pass membrane protein","id":"SL-9909"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33139539"}],"value":"Lysosome membrane","id":"SL-0157"},"topology":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24725410"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24782309"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24790029"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30095067"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30127360"}],"value":"Multi-pass membrane protein","id":"SL-9909"}}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10718198"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"14660746"}],"value":"Expressed in brain, kidney, ovary, lung, liver, heart, and fetal brain and liver. Found at high levels in bone marrow; lower levels are detected in peripheral blood cells. Expressed on T-cells as well as on B-lineage cells"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30095067"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30127360"}],"value":"The volume-regulated anion channel (VRAC) channel forms a trimer of dimers, with symmetry mismatch between the pore-forming domain and the cytosolic LRR repeats, a topology similar to gap junction proteins"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33139539"}],"value":"The di-leucine motif is required for lysosomal localization"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29925591"}],"value":"The cytoplasmic N-terminus preceding the first transmembrane (residues 1-22) regulates volume-regulated anion channel (VRAC) conductance, ion permeability and inactivation gating"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24790029"}],"value":"N-glycosylated"}],"commentType":"PTM"},{"commentType":"DISEASE","disease":{"diseaseId":"Agammaglobulinemia 5, autosomal dominant","diseaseAccession":"DI-02875","acronym":"AGM5","description":"A primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life.","diseaseCrossReference":{"database":"MIM","id":"613506"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"14660746"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving LRRC8 has been found in a patient with congenital agammaglobulinemia. Translocation t(9;20)(q33.2;q12). The translocation truncates the LRRC8 gene, resulting in deletion of the eighth, ninth, and half of the seventh LRR domains"}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Belongs to the LRRC8 family"}],"commentType":"SIMILARITY"},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Erroneous initiation","sequence":"AAQ88653.1","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Erroneous initiation","sequence":"BAA92675.1","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Erroneous initiation","sequence":"BAC11161.1","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"WEB RESOURCE","resourceName":"LRRC8Abase","resourceUrl":"https://databases.lovd.nl/shared/genes/LRRC8A","ftp":false,"note":"LRRC8A mutation 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