Protein: Volume-regulated anion channel subunit LRRC8A (Leucine-rich repeat-containing protein 8A) (HsLRRC8A) (Swelling protein 1) (Q8IWT6)
Organism: Homo sapiens (Human)
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. The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine. Mediates efflux of amino acids, such as aspartate and glutamate, in response to osmotic stress. LRRC8A and LRRC8D are required for the uptake of the drug cisplatin. 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. In contrast, complexes containing LRRC8D inhibit transport of 2'-3'-cGAMP. 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. Can form functional channels by itself (in vitro). Involved in B-cell development: required for the pro-B cell to pre-B cell transition. 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. 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.
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}.
Sequence: MIPVTELRYFADTQPAYRILKPWWDVFTDYISIVMLMIAVFGGTLQVTQDKMICLPCKWVTKDSCNDSFRGWAAPGPEPTYPNSTILPTPDTGPTGIKYDLDRHQYNYVDAVCYENRLHWFAKYFPYLVLLHTLIFLACSNFWFKFPRTSSKLEHFVSILLKCFDSPWTTRALSETVVEESDPKPAFSKMNGSMDKKSSTVSEDVEATVPMLQRTKSRIEQGIVDRSETGVLDKKEGEQAKALFEKVKKFRTHVEEGDIVYRLYMRQTIIKVIKFILIICYTVYYVHNIKFDVDCTVDIESLTGYRTYRCAHPLATLFKILASFYISLVIFYGLICMYTLWWMLRRSLKKYSFESIREESSYSDIPDVKNDFAFMLHLIDQYDPLYSKRFAVFLSEVSENKLRQLNLNNEWTLDKLRQRLTKNAQDKLELHLFMLSGIPDTVFDLVELEVLKLELIPDVTIPPSIAQLTGLKELWLYHTAAKIEAPALAFLRENLRALHIKFTDIKEIPLWIYSLKTLEELHLTGNLSAENNRYIVIDGLRELKRLKVLRLKSNLSKLPQVVTDVGVHLQKLSINNEGTKLIVLNSLKKMANLTELELIRCDLERIPHSIFSLHNLQEIDLKDNNLKTIEEIISFQHLHRLTCLKLWYNHIAYIPIQIGNLTNLERLYLNRNKIEKIPTQLFYCRKLRYLDLSHNNLTFLPADIGLLQNLQNLAITANRIETLPPELFQCRKLRALHLGNNVLQSLPSRVGELTNLTQIELRGNRLECLPVELGECPLLKRSGLVVEEDLFNTLPPEVKERLWRADKEQA
InterPro domains: - IPR032675: Leucine-rich repeat domain superfamily (homologous_superfamily) [390-802]
- IPR055414: Disease resistance R13L4/SHOC-2-like, LRR domain (domain) [685-764]
- IPR003591: Leucine-rich repeat, typical subtype (repeat) [590-776]
- IPR001611: Leucine-rich repeat (repeat) [592-707]
- IPR021040: LRRC8, pannexin-like TM region (domain) [1-340]
- IPR050216: Leucine-rich repeat domain-containing protein (family) [570-798]
Interaction partners: - Volume-regulated anion channel subunit LRRC8C
- Volume-regulated anion channel subunit LRRC8E
- Volume-regulated anion channel subunit LRRC8B
- Volume-regulated anion channel subunit LRRC8D
- Immunoglobulin lambda-like polypeptide 1
- Bestrophin-1
- Anoctamin-1
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0005215 (transporter activity), GO:0022857 (transmembrane transporter activity), GO:0005515 (protein binding), GO:0015075 (monoatomic ion transmembrane transporter activity), GO:0022803 (passive transmembrane transporter activity), GO:0005216 (monoatomic ion channel activity), GO:0008509 (monoatomic anion transmembrane transporter activity), GO:0015267 (channel activity), GO:0005253 (monoatomic anion channel activity)
Biological Process (BP): GO:0008150 (biological process), GO:0051179 (localization), GO:0009987 (cellular process), GO:0055085 (transmembrane transport), GO:0051234 (establishment of localization), GO:0098739 (import across plasma membrane), GO:0006810 (transport), GO:1901679 (nucleotide transmembrane transport), GO:0072530 (purine-containing compound transmembrane transport), GO:0034220 (monoatomic ion transmembrane transport), GO:0098657 (import into cell), GO:0071705 (nitrogen compound transport), GO:0071702 (organic substance transport), GO:0098656 (monoatomic anion transmembrane transport), GO:0006811 (monoatomic ion transport), GO:0015931 (nucleobase-containing compound transport), GO:0015748 (organophosphate ester transport), GO:1901264 (carbohydrate derivative transport), GO:0015711 (organic anion transport), GO:0006820 (monoatomic anion transport), GO:0006862 (nucleotide transport), GO:0015868 (purine ribonucleotide transport), GO:0015865 (purine nucleotide transport), GO:0051503 (adenine nucleotide transport)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0032991 (protein-containing complex), GO:0005622 (intracellular anatomical structure), GO:0005737 (cytoplasm), GO:0071944 (cell periphery), GO:0016020 (membrane), GO:0098796 (membrane protein complex), GO:1990351 (transporter complex), GO:1902495 (transmembrane transporter complex), GO:0005886 (plasma membrane), GO:0034702 (ion channel complex)