LRRC8A
entrez
56262
canonical
uniprot
Q8IWT6
canonical
ensembl
ENSG00000136802
resolver
ensp
ENSP00000259324
resolver
ensp
ENSP00000361680
resolver
ensp
ENSP00000361682
resolver
ensp
ENSP00000537261
resolver
ensp
ENSP00000537262
resolver
ensp
ENSP00000537263
resolver
ensp
ENSP00000537264
resolver
ensp
ENSP00000537265
resolver
ensp
ENSP00000537266
resolver
ensp
ENSP00000537267
resolver
ensp
ENSP00000537268
resolver
ensp
ENSP00000537269
resolver
ensp
ENSP00000537270
resolver
ensp
ENSP00000537271
resolver
ensp
ENSP00000537272
resolver
ensp
ENSP00000537273
resolver
ensp
ENSP00000597525
resolver
ensp
ENSP00000597526
resolver
ensp
ENSP00000597527
resolver
ensp
ENSP00000597528
resolver
ensp
ENSP00000597529
resolver
ensp
ENSP00000597530
resolver
ensp
ENSP00000597531
resolver
ensp
ENSP00000597532
resolver
ensp
ENSP00000597533
resolver
ensp
ENSP00000597535
resolver
ensp
ENSP00000597536
resolver
ensp
ENSP00000634785
resolver
ensp
ENSP00000634786
resolver
ensp
ENSP00000634787
resolver
ensp
ENSP00000634788
resolver
ensp
ENSP00000634789
resolver
ensp
ENSP00000634790
resolver
ensp
ENSP00000634791
resolver
ensp
ENSP00000634792
resolver
ensp
ENSP00000634793
resolver
ensp
ENSP00000634794
resolver
enst
ENST00000259324
resolver
enst
ENST00000372599
resolver
enst
ENST00000372600
resolver
enst
ENST00000867202
resolver
enst
ENST00000867203
resolver
enst
ENST00000867204
resolver
enst
ENST00000867205
resolver
enst
ENST00000867206
resolver
enst
ENST00000867207
resolver
enst
ENST00000867208
resolver
enst
ENST00000867209
resolver
enst
ENST00000867210
resolver
enst
ENST00000867211
resolver
enst
ENST00000867212
resolver
enst
ENST00000867213
resolver
enst
ENST00000867214
resolver
enst
ENST00000927466
resolver
enst
ENST00000927467
resolver
enst
ENST00000927468
resolver
enst
ENST00000927469
resolver
enst
ENST00000927470
resolver
enst
ENST00000927471
resolver
enst
ENST00000927472
resolver
enst
ENST00000927473
resolver
enst
ENST00000927474
resolver
enst
ENST00000927476
resolver
enst
ENST00000927477
resolver
enst
ENST00000964726
resolver
enst
ENST00000964727
resolver
enst
ENST00000964728
resolver
enst
ENST00000964729
resolver
enst
ENST00000964730
resolver
enst
ENST00000964731
resolver
enst
ENST00000964732
resolver
enst
ENST00000964733
resolver
enst
ENST00000964734
resolver
enst
ENST00000964735
resolver
genesymbol
LRRC8A
resolver
genesymbol_syn
KIAA1437
resolver
genesymbol_syn
LRRC8
resolver
genesymbol_syn
SWELL1
resolver
hgnc
HGNC:19027
resolver
uniprot
A8K1C7
resolver
uniprot
Q6UXM2
resolver
uniprot
Q8NCI0
resolver
uniprot
Q9P2B1
resolver
uniprot_entry
A8K1C7_HUMAN
resolver
uniprot_entry
LRC8A_HUMAN
resolver
uniprot_sec
Q6UXM2
resolver
uniprot_sec
Q8NCI0
resolver
uniprot_sec
Q9P2B1
resolver
activity_regulation
ACTIVITY REGULATION: 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). {ECO:0000250|UniProtKB:Q80WG5}.
uniprot
proteins
amino_acid_sequence
MIPVTELRYFADTQPAYRILKPWWDVFTDYISIVMLMIAVFGGTLQVTQDKMICLPCKWVTKDSCNDSFRGWAAPGPEPTYPNSTILPTPDTGPTGIKYDLDRHQYNYVDAVCYENRLHWFAKYFPYLVLLHTLIFLACSNFWFKFPRTSSKLEHFVSILLKCFDSPWTTRALSETVVEESDPKPAFSKMNGSMDKKSSTVSEDVEATVPMLQRTKSRIEQGIVDRSETGVLDKKEGEQAKALFEKVKKFRTHVEEGDIVYRLYMRQTIIKVIKFILIICYTVYYVHNIKFDVDCTVDIESLTGYRTYRCAHPLATLFKILASFYISLVIFYGLICMYTLWWMLRRSLKKYSFESIREESSYSDIPDVKNDFAFMLHLIDQYDPLYSKRFAVFLSEVSENKLRQLNLNNEWTLDKLRQRLTKNAQDKLELHLFMLSGIPDTVFDLVELEVLKLELIPDVTIPPSIAQLTGLKELWLYHTAAKIEAPALAFLRENLRALHIKFTDIKEIPLWIYSLKTLEELHLTGNLSAENNRYIVIDGLRELKRLKVLRLKSNLSKLPQVVTDVGVHLQKLSINNEGTKLIVLNSLKKMANLTELELIRCDLERIPHSIFSLHNLQEIDLKDNNLKTIEEIISFQHLHRLTCLKLWYNHIAYIPIQIGNLTNLERLYLNRNKIEKIPTQLFYCRKLRYLDLSHNNLTFLPADIGLLQNLQNLAITANRIETLPPELFQCRKLRALHLGNNVLQSLPSRVGELTNLTQIELRGNRLECLPVELGECPLLKRSGLVVEEDLFNTLPPEVKERLWRADKEQA
uniprot
proteins
disease_involvement
DISEASE: Agammaglobulinemia 5, autosomal dominant (AGM5) [MIM:613506]: 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. {ECO:0000269|PubMed:14660746}. Note=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.
uniprot
proteins
function
FUNCTION: 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). {ECO:0000250|UniProtKB:Q80WG5, ECO:0000269|PubMed:14660746, ECO:0000269|PubMed:24725410, ECO:0000269|PubMed:24790029, ECO:0000269|PubMed:26530471, ECO:0000269|PubMed:26824658, ECO:0000269|PubMed:28193731, ECO:0000269|PubMed:29371604, ECO:0000269|PubMed:29769723, ECO:0000269|PubMed:30095067, ECO:0000269|PubMed:31270356, ECO:0000269|PubMed:33139539, ECO:0000269|PubMed:33171122, ECO:0000269|PubMed:39909992}.
uniprot
proteins
mass_dalton
94199
uniprot
proteins
mutagenesis
MUTAGEN 5; /note="T->C: No effect."; /evidence="ECO:0000269|PubMed:30095067"; MUTAGEN 5; /note="T->R: Anion channel is more selective to iodite compared to chloride."; /evidence="ECO:0000269|PubMed:30095067"; MUTAGEN 6; /note="E->C: Decreased amplitudes of swelling-activated currents."; /evidence="ECO:0000269|PubMed:29925591"; MUTAGEN 44; /note="T->A,C: Altered anion selectivity."; /evidence="ECO:0000269|PubMed:24725410"; MUTAGEN 66; /note="N->A: Abolishes N-glycosylation; when associated with A-83."; /evidence="ECO:0000269|PubMed:24790029"; MUTAGEN 83; /note="N->A: Abolishes N-glycosylation; when associated with A-66."; /evidence="ECO:0000269|PubMed:24790029"; MUTAGEN 103; /note="R->F: Affects ion selectivity of the channel."; /evidence="ECO:0000269|PubMed:30095067"; MUTAGEN 103; /note="R->L: Abolished ability to transport 2'-3'-cGAMP."; /evidence="ECO:0000269|PubMed:33171122"; MUTAGEN 706..707; /note="LL->AA: Abolished localization to lysosomes."; /evidence="ECO:0000269|PubMed:33139539
uniprot
proteins
post_translational_modification
PTM: N-glycosylated. {ECO:0000269|PubMed:24790029}.
uniprot
proteins
protein_family
LRRC8 family
uniprot
proteins
pubmed
10718198
uniprot
proteins
pubmed
12975309
uniprot
proteins
pubmed
14660746
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15164053
uniprot
proteins
pubmed
15183935
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
17081983
uniprot
proteins
pubmed
21406692
uniprot
proteins
pubmed
22532330
uniprot
proteins
pubmed
22814378
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
24725410
uniprot
proteins
pubmed
24782309
uniprot
proteins
pubmed
24790029
uniprot
proteins
pubmed
26530471
uniprot
proteins
pubmed
26824658
uniprot
proteins
pubmed
28193731
uniprot
proteins
pubmed
29371604
uniprot
proteins
pubmed
29769723
uniprot
proteins
pubmed
29925591
uniprot
proteins
pubmed
30095067
uniprot
proteins
pubmed
30127360
uniprot
proteins
pubmed
30135305
uniprot
proteins
pubmed
31270356
uniprot
proteins
pubmed
33139539
uniprot
proteins
pubmed
33171122
uniprot
proteins
pubmed
36897307
uniprot
proteins
pubmed
39909992
uniprot
proteins
sequence_length
810
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:24725410, ECO:0000269|PubMed:24782309, ECO:0000269|PubMed:24790029, ECO:0000269|PubMed:26824658, ECO:0000305|PubMed:29769723}; Multi-pass membrane protein {ECO:0000269|PubMed:24725410, ECO:0000269|PubMed:24782309, ECO:0000269|PubMed:24790029, ECO:0000269|PubMed:30095067, ECO:0000269|PubMed:30127360}. Lysosome membrane {ECO:0000269|PubMed:33139539}; Multi-pass membrane protein {ECO:0000269|PubMed:24725410, ECO:0000269|PubMed:24782309, ECO:0000269|PubMed:24790029, ECO:0000269|PubMed:30095067, ECO:0000269|PubMed:30127360}. Note=Mainly localizes to the cell membrane, with some intracellular localization to lysosomes. {ECO:0000269|PubMed:33139539}.
uniprot
proteins
transmembrane_region
TRANSMEM 24..47; /note="Helical; Name=1"; /evidence="ECO:0000305|PubMed:30095067, ECO:0000305|PubMed:30127360, ECO:0007744|PDB:5ZSU, ECO:0007744|PDB:6DJB"; TRANSMEM 124..142; /note="Helical; Name=2"; /evidence="ECO:0000305|PubMed:30095067, ECO:0000305|PubMed:30127360, ECO:0007744|PDB:5ZSU, ECO:0007744|PDB:6DJB"; TRANSMEM 265..286; /note="Helical; Name=3"; /evidence="ECO:0000305|PubMed:30095067, ECO:0000305|PubMed:30127360, ECO:0007744|PDB:5ZSU, ECO:0007744|PDB:6DJB"; TRANSMEM 317..341; /note="Helical; Name=4"; /evidence="ECO:0000305|PubMed:30095067, ECO:0000305|PubMed:30127360, ECO:0007744|PDB:5ZSU, ECO:0007744|PDB:6DJB
uniprot
proteins