Lrrc8a
entrez
241296
canonical
uniprot
Q80WG5
canonical
ensembl
ENSMUSG00000007476
resolver
ensembl
ENSMUSG00000099041
resolver
ensp
ENSMUSP00000092690
resolver
ensp
ENSMUSP00000109284
resolver
ensp
ENSMUSP00000139038
resolver
enst
ENSMUST00000095078
resolver
enst
ENSMUST00000113654
resolver
enst
ENSMUST00000139454
resolver
genesymbol
Lrrc8a
resolver
genesymbol_syn
Lrrc8
resolver
genesymbol_syn
Swell1
resolver
uniprot
A2AQZ0
resolver
uniprot_entry
LRC8A_MOUSE
resolver
uniprot_sec
A2AQZ0
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 (PubMed:30775971). Lipids may block conduction in closed heterohexameric channels (PubMed:36928458). {ECO:0000269|PubMed:30775971, ECO:0000269|PubMed:36928458}.
uniprot
proteins
amino_acid_sequence
MIPVTELRYFADTQPAYRILKPWWDVFTDYISIVMLMIAVFGGTLQVTQDKMICLPCKWVTKDSCNDSFRGWAASSPEPTYPNSTVLPTPDTGPTGIKYDLDRHQYNYVDAVCYENRLHWFAKYFPYLVLLHTLIFLACSNFWFKFPRTSSKLEHFVSILLKCFDSPWTTRALSETVVEESDPKPAFSKMNGSMDKKSSTVSEDVEATVPMLQRTKSRIEQGIVDRSETGVLDKKEGEQAKALFEKVKKFRTHVEEGDIVYRLYMRQTIIKVIKFALIICYTVYYVHNIKFDVDCTVDIESLTGYRTYRCAHPLATLFKILASFYISLVIFYGLICMYTLWWMLRRSLKKYSFESIREESSYSDIPDVKNDFAFMLHLIDQYDPLYSKRFAVFLSEVSENKLRQLNLNNEWTLDKLRQRLTKNAQDKLELHLFMLSGIPDTVFDLVELEVLKLELIPDVTIPPSIAQLTGLKELWLYHTAAKIEAPALAFLRENLRALHIKFTDIKEIPLWIYSLKTLEELHLTGNLSAENNRYIVIDGLRELKRLKVLRLKSNLSKLPQVVTDVGVHLQKLSINNEGTKLIVLNSLKKMVNLTELELIRCDLERIPHSIFSLHNLQEIDLKDNNLKTIEEIISFQHLHRLTCLKLWYNHIAYIPIQIGNLTNLERLYLNRNKIEKIPTQLFYCRKLRYLDLSHNNLTFLPADIGLLQNLQNLAVTANRIEALPPELFQCRKLRALHLGNNVLQSLPSRVGELTNLTQIELRGNRLECLPVELGECPLLKRSGLVVEEDLFSTLPPEVKERLWRADKEQA
uniprot
proteins
disease_involvement
DISEASE: Note=Defects in Lrrc8a are the cause of ebouriffe (ebo), a spontaneous mutation that causes male sterility (PubMed:28192143, PubMed:30135305, PubMed:8828840). Spermatozoa present in the epididymis display severe malformations, mostly of the tail (PubMed:28192143, PubMed:8828840). A drastic decrease of the spermatid population is observed, whereas spermatogonia and spermatocytes seem moderately affected (PubMed:28192143, PubMed:8828840). Defects are caused by decreased volume-regulated anion channel (VRAC) activity in germ cells (PubMed:30135305). Oogenesis is not affected but embryos derived from ebo/ebo females show early developmental failure (PubMed:30135305). {ECO:0000269|PubMed:28192143, ECO:0000269|PubMed:30135305, ECO:0000269|PubMed:8828840}.
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:29769723, PubMed:30135305, PubMed:36522427, PubMed:36928458). The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine (By similarity). Mediates efflux of amino acids, such as aspartate and glutamate, in response to osmotic stress (By similarity). 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:32277911). In contrast, complexes containing LRRC8D inhibit transport of 2'-3'-cGAMP (By similarity). 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:36522427, PubMed:36928458). Can form functional channels by itself (in vitro) (By similarity). Involved in B-cell development: required for the pro-B cell to pre-B cell transition (PubMed:14660746, PubMed:24752297). Also required for T-cell development (PubMed:24752297). Required for myoblast differentiation: VRAC activity promotes membrane hyperpolarization and regulates insulin-stimulated glucose metabolism and oxygen consumption (PubMed:31387946, PubMed:32930093). 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, PubMed:29773801). 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 (By similarity). Acts as a key factor in NLRP3 inflammasome activation by modulating itaconate efflux and mitochondria function (PubMed:38006980). {ECO:0000250|UniProtKB:Q8IWT6, ECO:0000269|PubMed:14660746, ECO:0000269|PubMed:24752297, ECO:0000269|PubMed:29371604, ECO:0000269|PubMed:29769723, ECO:0000269|PubMed:29773801, ECO:0000269|PubMed:30135305, ECO:0000269|PubMed:31387946, ECO:0000269|PubMed:32277911, ECO:0000269|PubMed:32930093, ECO:0000269|PubMed:36522427, ECO:0000269|PubMed:36928458}.
uniprot
proteins
mass_dalton
94120
uniprot
proteins
mutagenesis
MUTAGEN 40; /note="V->D: Abolishes activity in hypotonic solution."; /evidence="ECO:0000269|PubMed:36928458"; MUTAGEN 44; /note="T->D: Abolishes activity in hypotonic solution."; /evidence="ECO:0000269|PubMed:36928458"; MUTAGEN 47; /note="V->D: Abolishes activity in hypotonic solution."; /evidence="ECO:0000269|PubMed:36928458"; MUTAGEN 47; /note="V->K,N: Impairs activity in hypotonic solution."; /evidence="ECO:0000269|PubMed:36928458"; MUTAGEN 48; /note="T->D: Abolishes activity in hypotonic solution."; /evidence="ECO:0000269|PubMed:36928458"; MUTAGEN 48; /note="T->W,Y,K,N: Impairs activity in hypotonic solution."; /evidence="ECO:0000269|PubMed:36928458"; MUTAGEN 103; /note="R->A: No effect on anion channel activity. Impairs channel selectivity, so that the channel is also permeable to Na(+) ions."; /evidence="ECO:0000269|PubMed:29769723
uniprot
proteins
post_translational_modification
PTM: N-glycosylated. {ECO:0000250|UniProtKB:Q8IWT6}.
uniprot
proteins
protein_family
LRRC8 family
uniprot
proteins
pubmed
14660746
uniprot
proteins
pubmed
15094057
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
19468303
uniprot
proteins
pubmed
21183079
uniprot
proteins
pubmed
24725410
uniprot
proteins
pubmed
24752297
uniprot
proteins
pubmed
24782309
uniprot
proteins
pubmed
28192143
uniprot
proteins
pubmed
29371604
uniprot
proteins
pubmed
29769723
uniprot
proteins
pubmed
29773801
uniprot
proteins
pubmed
29880644
uniprot
proteins
pubmed
30135305
uniprot
proteins
pubmed
30775971
uniprot
proteins
pubmed
31387946
uniprot
proteins
pubmed
32277911
uniprot
proteins
pubmed
32930093
uniprot
proteins
pubmed
36522427
uniprot
proteins
pubmed
36928458
uniprot
proteins
pubmed
38006980
uniprot
proteins
pubmed
8828840
uniprot
proteins
sequence_length
810
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:24782309, ECO:0000269|PubMed:29769723, ECO:0000269|PubMed:30135305}; Multi-pass membrane protein {ECO:0000269|PubMed:29769723, ECO:0000269|PubMed:30775971}. Lysosome membrane {ECO:0000250|UniProtKB:Q8IWT6}; Multi-pass membrane protein {ECO:0000269|PubMed:29769723, ECO:0000269|PubMed:30775971}. Note=Mainly localizes to the cell membrane, with some intracellular localization to lysosomes. {ECO:0000250|UniProtKB:Q8IWT6}.
uniprot
proteins
transmembrane_region
TRANSMEM 23..47; /note="Helical; Name=1"; /evidence="ECO:0000269|PubMed:30775971, ECO:0000269|PubMed:36522427, ECO:0000269|PubMed:36928458, ECO:0007744|PDB:6NZW, ECO:0007744|PDB:6NZZ, ECO:0007744|PDB:6O00, ECO:0007744|PDB:8B41, ECO:0007744|PDB:8B42, ECO:0007744|PDB:8DRK"; TRANSMEM 124..142; /note="Helical; Name=2"; /evidence="ECO:0000269|PubMed:30775971, ECO:0000269|PubMed:36522427, ECO:0000269|PubMed:36928458, ECO:0007744|PDB:6NZW, ECO:0007744|PDB:6NZZ, ECO:0007744|PDB:6O00, ECO:0007744|PDB:8B41, ECO:0007744|PDB:8B42, ECO:0007744|PDB:8DRK"; TRANSMEM 265..286; /note="Helical; Name=3"; /evidence="ECO:0000269|PubMed:30775971, ECO:0000269|PubMed:36522427, ECO:0000269|PubMed:36928458, ECO:0007744|PDB:6NZW, ECO:0007744|PDB:6NZZ, ECO:0007744|PDB:6O00, ECO:0007744|PDB:8B41, ECO:0007744|PDB:8B42, ECO:0007744|PDB:8DRK"; TRANSMEM 317..341; /note="Helical; Name=4"; /evidence="ECO:0000269|PubMed:30775971, ECO:0000269|PubMed:36522427, ECO:0000269|PubMed:36928458, ECO:0007744|PDB:6NZW, ECO:0007744|PDB:6NZZ, ECO:0007744|PDB:6O00, ECO:0007744|PDB:8B41, ECO:0007744|PDB:8B42, ECO:0007744|PDB:8DRK
uniprot
proteins