LRC8A_RAT
ID LRC8A_RAT Reviewed; 810 AA.
AC Q4V8I7;
DT 07-FEB-2006, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 124.
DE RecName: Full=Volume-regulated anion channel subunit LRRC8A {ECO:0000305};
DE AltName: Full=Leucine-rich repeat-containing protein 8A {ECO:0000303|PubMed:28833202};
GN Name=Lrrc8a {ECO:0000303|PubMed:28833202, ECO:0000312|RGD:1311690};
GN Synonyms=Lrrc8 {ECO:0000303|PubMed:28833202};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [2]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-202 AND SER-217, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [3]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND SUBUNIT.
RX PubMed=28833202; DOI=10.1113/jp275053;
RA Schober A.L., Wilson C.S., Mongin A.A.;
RT "Molecular composition and heterogeneity of the LRRC8-containing swelling-
RT activated osmolyte channels in primary rat astrocytes.";
RL J. Physiol. (Lond.) 595:6939-6951(2017).
CC -!- FUNCTION: Essential component of the volume-regulated anion channel
CC (VRAC, also named VSOAC channel), an anion channel required to maintain
CC a constant cell volume in response to extracellular or intracellular
CC osmotic changes (PubMed:28833202). The VRAC channel conducts iodide
CC better than chloride and can also conduct organic osmolytes like
CC taurine (PubMed:28833202). Mediates efflux of amino acids, such as
CC aspartate and glutamate, in response to osmotic stress (By similarity).
CC In complex with LRRC8C or LRRC8E, acts as a transporter of
CC immunoreactive cyclic dinucleotide GMP-AMP (2'-3'-cGAMP), an immune
CC messenger produced in response to DNA virus in the cytosol: mediates
CC both import and export of 2'-3'-cGAMP, thereby promoting transfer of
CC 2'-3'-cGAMP to bystander cells (By similarity). In contrast, complexes
CC containing LRRC8D inhibit transport of 2'-3'-cGAMP (By similarity).
CC Required for in vivo channel activity, together with at least one other
CC family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel
CC characteristics depend on the precise subunit composition
CC (PubMed:28833202). Can form functional channels by itself (in vitro)
CC (By similarity). Involved in B-cell development: required for the pro-B
CC cell to pre-B cell transition (By similarity). Also required for T-cell
CC development (By similarity). Required for myoblast differentiation:
CC VRAC activity promotes membrane hyperpolarization and regulates
CC insulin-stimulated glucose metabolism and oxygen consumption (By
CC similarity). Also acts as a regulator of glucose-sensing in pancreatic
CC beta cells: VRAC currents, generated in response to hypotonicity- or
CC glucose-induced beta cell swelling, depolarize cells, thereby causing
CC electrical excitation, leading to increase glucose sensitivity and
CC insulin secretion (By similarity). Also plays a role in lysosome
CC homeostasis by forming functional lysosomal VRAC channels in response
CC to low cytoplasmic ionic strength condition: lysosomal VRAC channels
CC are necessary for the formation of large lysosome-derived vacuoles,
CC which store and then expel excess water to maintain cytosolic water
CC homeostasis (By similarity). {ECO:0000250|UniProtKB:Q80WG5,
CC ECO:0000250|UniProtKB:Q8IWT6, ECO:0000269|PubMed:28833202}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=chloride(in) = chloride(out); Xref=Rhea:RHEA:29823,
CC ChEBI:CHEBI:17996; Evidence={ECO:0000250|UniProtKB:Q8IWT6};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=iodide(out) = iodide(in); Xref=Rhea:RHEA:66324,
CC ChEBI:CHEBI:16382; Evidence={ECO:0000250|UniProtKB:Q8IWT6};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=taurine(out) = taurine(in); Xref=Rhea:RHEA:66328,
CC ChEBI:CHEBI:507393; Evidence={ECO:0000269|PubMed:28833202};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-aspartate(out) = L-aspartate(in); Xref=Rhea:RHEA:66332,
CC ChEBI:CHEBI:29991; Evidence={ECO:0000305|PubMed:28833202};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-glutamate(out) = L-glutamate(in); Xref=Rhea:RHEA:66336,
CC ChEBI:CHEBI:29985; Evidence={ECO:0000250|UniProtKB:Q8IWT6};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=myo-inositol(out) = myo-inositol(in); Xref=Rhea:RHEA:32867,
CC ChEBI:CHEBI:17268; Evidence={ECO:0000269|PubMed:28833202};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2',3'-cGAMP(out) = 2',3'-cGAMP(in); Xref=Rhea:RHEA:66320,
CC ChEBI:CHEBI:143093; Evidence={ECO:0000250|UniProtKB:Q8IWT6};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66321;
CC Evidence={ECO:0000250|UniProtKB:Q8IWT6};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:66322;
CC Evidence={ECO:0000250|UniProtKB:Q8IWT6};
CC -!- ACTIVITY REGULATION: Inhibited by (4-[(2-butyl-6,7-dichloro-2-
CC cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]butanoic acid), which
CC plugs the channel like a cork in a bottle by binding in the
CC extracellular selectivity filter and sterically occluding ion
CC conduction. {ECO:0000250|UniProtKB:Q80WG5}.
CC -!- SUBUNIT: Hexamer; forms a trimer of dimers (By similarity).
CC Heterohexamer; oligomerizes with other LRRC8 proteins (LRRC8B, LRRC8C,
CC LRRC8D and/or LRRC8E) to form a heterohexamer (By similarity). Can form
CC homohexamers in vitro, but these have lower conductance than
CC heterohexamers (By similarity). Detected in a channel complex that
CC contains LRRC8A, LRRC8C and LRRC8E (By similarity). In vivo, the
CC subunit composition may depend primarily on expression levels, and
CC heterooligomeric channels containing various proportions of the
CC different LRRC8 proteins may coexist (PubMed:28833202). Interact with
CC GRB2 (By similarity). {ECO:0000250|UniProtKB:Q80WG5,
CC ECO:0000250|UniProtKB:Q8IWT6, ECO:0000269|PubMed:28833202}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000305|PubMed:28833202};
CC Multi-pass membrane protein {ECO:0000250|UniProtKB:Q8IWT6}. Lysosome
CC membrane {ECO:0000250|UniProtKB:Q8IWT6}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q8IWT6}. Note=Mainly localizes to the cell
CC membrane, with some intracellular localization to lysosomes.
CC {ECO:0000250|UniProtKB:Q8IWT6}.
CC -!- DOMAIN: The volume-regulated anion channel (VRAC) channel forms a
CC trimer of dimers, with symmetry mismatch between the pore-forming
CC domain and the cytosolic LRR repeats, a topology similar to gap
CC junction proteins. {ECO:0000250|UniProtKB:Q8IWT6}.
CC -!- DOMAIN: The di-leucine motif is required for lysosomal localization.
CC {ECO:0000250|UniProtKB:Q8IWT6}.
CC -!- DOMAIN: The cytoplasmic N-terminus preceding the first transmembrane
CC (residues 1-22) regulates volume-regulated anion channel (VRAC)
CC conductance, ion permeability and inactivation gating.
CC {ECO:0000250|UniProtKB:Q8IWT6}.
CC -!- PTM: N-glycosylated. {ECO:0000250|UniProtKB:Q8IWT6}.
CC -!- SIMILARITY: Belongs to the LRRC8 family. {ECO:0000305}.
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DR EMBL; BC097371; AAH97371.1; -; mRNA.
DR RefSeq; NP_001019953.1; NM_001024782.1.
DR RefSeq; XP_017447329.1; XM_017591840.1.
DR RefSeq; XP_017447330.1; XM_017591841.1.
DR RefSeq; XP_017447331.1; XM_017591842.1.
DR RefSeq; XP_017447332.1; XM_017591843.1.
DR AlphaFoldDB; Q4V8I7; -.
DR SMR; Q4V8I7; -.
DR STRING; 10116.ENSRNOP00000031726; -.
DR GlyGen; Q4V8I7; 2 sites.
DR iPTMnet; Q4V8I7; -.
DR PhosphoSitePlus; Q4V8I7; -.
DR jPOST; Q4V8I7; -.
DR PaxDb; Q4V8I7; -.
DR PRIDE; Q4V8I7; -.
DR Ensembl; ENSRNOT00000033934; ENSRNOP00000031726; ENSRNOG00000025296.
DR GeneID; 311846; -.
DR KEGG; rno:311846; -.
DR UCSC; RGD:1311690; rat.
DR CTD; 56262; -.
DR RGD; 1311690; Lrrc8a.
DR eggNOG; KOG0619; Eukaryota.
DR GeneTree; ENSGT00940000154043; -.
DR HOGENOM; CLU_019019_0_0_1; -.
DR InParanoid; Q4V8I7; -.
DR OMA; HNVQEID; -.
DR OrthoDB; 158390at2759; -.
DR PhylomeDB; Q4V8I7; -.
DR TreeFam; TF331443; -.
DR Reactome; R-RNO-5223345; Miscellaneous transport and binding events.
DR PRO; PR:Q4V8I7; -.
DR Proteomes; UP000002494; Chromosome 3.
DR Bgee; ENSRNOG00000025296; Expressed in heart and 19 other tissues.
DR Genevisible; Q4V8I7; RN.
DR GO; GO:0009986; C:cell surface; ISO:RGD.
DR GO; GO:1905103; C:integral component of lysosomal membrane; ISS:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; ISS:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IMP:UniProtKB.
DR GO; GO:0034702; C:ion channel complex; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0140360; F:cyclic-GMP-AMP transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0005225; F:volume-sensitive anion channel activity; IMP:UniProtKB.
DR GO; GO:0098656; P:anion transmembrane transport; ISS:UniProtKB.
DR GO; GO:0006820; P:anion transport; ISS:UniProtKB.
DR GO; GO:0015810; P:aspartate transmembrane transport; IMP:UniProtKB.
DR GO; GO:0006884; P:cell volume homeostasis; ISS:UniProtKB.
DR GO; GO:0001678; P:cellular glucose homeostasis; ISS:UniProtKB.
DR GO; GO:1902476; P:chloride transmembrane transport; ISS:UniProtKB.
DR GO; GO:0140361; P:cyclic-GMP-AMP transmembrane import across plasma membrane; ISS:UniProtKB.
DR GO; GO:0032024; P:positive regulation of insulin secretion; ISS:UniProtKB.
DR GO; GO:0045663; P:positive regulation of myoblast differentiation; ISS:UniProtKB.
DR GO; GO:0002329; P:pre-B cell differentiation; ISS:UniProtKB.
DR GO; GO:0034214; P:protein hexamerization; ISS:UniProtKB.
DR GO; GO:0006970; P:response to osmotic stress; IMP:UniProtKB.
DR GO; GO:0007283; P:spermatogenesis; ISS:UniProtKB.
DR GO; GO:0015734; P:taurine transport; IMP:UniProtKB.
DR Gene3D; 3.80.10.10; -; 2.
DR InterPro; IPR001611; Leu-rich_rpt.
DR InterPro; IPR003591; Leu-rich_rpt_typical-subtyp.
DR InterPro; IPR032675; LRR_dom_sf.
DR InterPro; IPR021040; LRRC8_Pannexin-like.
DR Pfam; PF13855; LRR_8; 3.
DR Pfam; PF12534; Pannexin_like; 1.
DR SMART; SM00369; LRR_TYP; 8.
DR PROSITE; PS51450; LRR; 11.
PE 1: Evidence at protein level;
KW Acetylation; Cell membrane; Differentiation; Disulfide bond; Glycoprotein;
KW Ion channel; Ion transport; Leucine-rich repeat; Lysosome; Membrane;
KW Phosphoprotein; Reference proteome; Repeat; Spermatogenesis; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..810
FT /note="Volume-regulated anion channel subunit LRRC8A"
FT /id="PRO_0000084501"
FT TOPO_DOM 1..22
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q80WG5"
FT TRANSMEM 23..47
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q80WG5"
FT TOPO_DOM 48..123
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q80WG5"
FT TRANSMEM 124..142
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q80WG5"
FT TOPO_DOM 143..264
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q80WG5"
FT TRANSMEM 265..286
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q80WG5"
FT TOPO_DOM 287..316
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q80WG5"
FT TRANSMEM 317..341
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q80WG5"
FT TOPO_DOM 342..810
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q80WG5"
FT REPEAT 399..422
FT /note="LRR 1"
FT /evidence="ECO:0000255"
FT REPEAT 423..445
FT /note="LRR 2"
FT /evidence="ECO:0000255"
FT REPEAT 447..468
FT /note="LRR 3"
FT /evidence="ECO:0000255"
FT REPEAT 469..492
FT /note="LRR 4"
FT /evidence="ECO:0000255"
FT REPEAT 493..515
FT /note="LRR 5"
FT /evidence="ECO:0000255"
FT REPEAT 518..542
FT /note="LRR 6"
FT /evidence="ECO:0000255"
FT REPEAT 543..565
FT /note="LRR 7"
FT /evidence="ECO:0000255"
FT REPEAT 567..589
FT /note="LRR 8"
FT /evidence="ECO:0000255"
FT REPEAT 590..613
FT /note="LRR 9"
FT /evidence="ECO:0000255"
FT REPEAT 614..637
FT /note="LRR 10"
FT /evidence="ECO:0000255"
FT REPEAT 639..661
FT /note="LRR 11"
FT /evidence="ECO:0000255"
FT REPEAT 662..684
FT /note="LRR 12"
FT /evidence="ECO:0000255"
FT REPEAT 686..707
FT /note="LRR 13"
FT /evidence="ECO:0000255"
FT REPEAT 708..730
FT /note="LRR 14"
FT /evidence="ECO:0000255"
FT REPEAT 732..753
FT /note="LRR 15"
FT /evidence="ECO:0000255"
FT REPEAT 754..776
FT /note="LRR 16"
FT /evidence="ECO:0000255"
FT REPEAT 778..801
FT /note="LRR 17"
FT /evidence="ECO:0000255"
FT MOTIF 706..707
FT /note="Di-leucine motif"
FT /evidence="ECO:0000250|UniProtKB:Q8IWT6"
FT SITE 103
FT /note="Required for anion selectivity"
FT /evidence="ECO:0000250|UniProtKB:Q8IWT6"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000250|UniProtKB:Q8IWT6"
FT MOD_RES 200
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q80WG5"
FT MOD_RES 202
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 215
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q8IWT6"
FT MOD_RES 217
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT CARBOHYD 66
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 83
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 54..310
FT /evidence="ECO:0000250|UniProtKB:Q80WG5"
FT DISULFID 57..65
FT /evidence="ECO:0000250|UniProtKB:Q80WG5"
FT DISULFID 113..295
FT /evidence="ECO:0000250|UniProtKB:Q80WG5"
SQ SEQUENCE 810 AA; 94162 MW; A05EE234C10615C0 CRC64;
MIPVTELRYF ADTQPAYRIL KPWWDVFTDY ISIVMLMIAV FGGTLQVTQD KMICLPCKWV
TKDSCNDSFR GWGASSPEPT YPNSTVLPTP DTGPTGIKYD LDRHQYNYVD AVCYENRLHW
FAKYFPYLVL LHTLIFLACS NFWFKFPRTS SKLEHFVSIL LKCFDSPWTT RALSETVVEE
SDPKPAFSKM NGSMDKKSST VSEDVEATVP MLQRTKSRIE QGIVDRSETG VLDKKEGEQA
KALFEKVKKF RTHVEEGDIV YRLYMRQTII KVIKFFLIIC YTVYYVHNIK FDVDCTVDIE
SLTGYRTYRC AHPLATLFKI LASFYISLVI FYGLICMYTL WWMLRRSLKK YSFESIREES
SYSDIPDVKN DFAFMLHLID QYDPLYSKRF AVFLSEVSEN KLRQLNLNNE WTLDKLRQRL
TKNAQDKLEL HLFMLSGIPD TVFDLLELEV LKLELIPDVT IPPSIAQLTG LKELWLYHTA
AKIEAPALAF LRENLRALHI KFTDIKEIPL WIYSLKTLEE LHLTGNLSAE NNRYIVIDGL
RELKRLKVLR LKSNLSKLPQ VVTDVGVHLQ KLSINNEGTK LIVLNSLKKM VNLTELELIR
CDLERIPHSI FSLHNLQEID LKDNNLKTIE EIISFQHLHR LTCLKLWYNH IAYIPIQIGN
LTNLERLYLN RNKIEKIPTQ LFYCRKLRYL DLSHNNLTLL PADIGLLQNL QNLAVTANRI
EALPPELFQC RKLRALHLGN NVLQSLPSRV GELTNLTQIE LRGNRLECLP VELGECPLLK
RSGLVVEEDL FSTLPPEVKE RLWRADKEQA
