LRRC8A

Leucine-rich repeat-containing protein 8A is a protein that in humans is encoded by the LRRC8A gene.[5] Researchers have found out that this protein, along with the other LRRC8 proteins LRRC8B, LRRC8C, LRRC8D, and LRRC8E, is a subunit of the heteromer protein volume-regulated anion channel (VRAC).[6] (VRACs) are crucial to the regulation of cell size by transporting chloride ions and various organic osmolytes, such as taurine or glutamate, across the plasma membrane,[7] and that is not the only function these channels have been linked to.

LRRC8A
Identifiers
Aliases	LRRC8A, AGM5, LRRC8, SWELL1, leucine-rich repeat containing 8 family member A, leucine rich repeat containing 8 family member A, leucine rich repeat containing 8 VRAC subunit A
External IDs	OMIM: 608360 MGI: 2652847 HomoloGene: 18617 GeneCards: LRRC8A
Gene location (Human) Chr. Chromosome 9 (human)[1] Band 9q34.11 Start 128,882,112 bp[1] End 128,918,039 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2|2 B Start 30,237,715 bp[2] End 30,263,790 bp[2]
Gene ontology Molecular function • anion channel activity • GO:0001948 protein binding • volume-sensitive anion channel activity • identical protein binding Cellular component • integral component of membrane • cell surface • ion channel complex • membrane • cytoplasm • cell membrane • integral component of plasma membrane Biological process • pre-B cell differentiation • response to osmotic stress • cell volume homeostasis • cell differentiation • ion transport • anion transport • regulation of anion transport • anion transmembrane transport • signal transduction • transmembrane transport • transport • inorganic anion transport • taurine transport • aspartate transport • protein hexamerization Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	56262	241296
Ensembl	ENSG00000136802	ENSMUSG00000007476
UniProt	Q8IWT6	Q80WG5
RefSeq (mRNA)	NM_001127244 NM_001127245 NM_019594	NM_177725
RefSeq (protein)	NP_001120716 NP_001120717 NP_062540	NP_808393
Location (UCSC)	Chr 9: 128.88 – 128.92 Mb	Chr 2: 30.24 – 30.26 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

While LRRC8A is one of many proteins that can be part of VRAC, it is the most important subunit for the channel’s ability to function.[8][9] However, while we know it is necessary for VRAC function, other studies have found that it is not sufficient for the full range of usual VRAC activity.[10] This is where the other LRRC8 proteins come in, as the different composition of these subunits affects the range of specificity for VRACs.[11][12]

The transmembrane portion of LRRC8 proteins are similar to those in Pannexins.[13] LRRC8A alone can form a hexameric VRAC, for which the cyro-EM structure has been determined in its mice and human versions.[14][15][16]

In addition to its role in VRACs, the LRRC8 protein family is also associated with agammaglobulinemia-5.[17]

References

1. GRCh38: Ensembl release 89: ENSG00000136802 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000007476 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: LRRC8A leucine rich repeat containing 8 family, member A".
6. Voss FK, Ullrich F, Münch J, Lazarow K, Lutter D, Mah N, Andrade-Navarro MA, von Kries JP, Stauber T, Jentsch TJ (May 2014). "Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC" (PDF). Science. 344 (6184): 634–8. Bibcode:2014Sci...344..634V. doi:10.1126/science.1252826. PMID 24790029. S2CID 24709412.
7. Jentsch TJ (May 2016). "VRACs and other ion channels and transporters in the regulation of cell volume and beyond". Nature Reviews Molecular Cell Biology. 17 (5): 293–307. doi:10.1038/nrm.2016.29. PMID 27033257. S2CID 40565653.
8. Hyzinski-García MC, Rudkouskaya A, Mongin AA (November 2014). "LRRC8A protein is indispensable for swelling-activated and ATP-induced release of excitatory amino acids in rat astrocytes". The Journal of Physiology. 592 (22): 4855–62. doi:10.1113/jphysiol.2014.278887. PMC 4259531. PMID 25172945.
9. Yamada T, Wondergem R, Morrison R, Yin VP, Strange K (October 2016). "Leucine-rich repeat containing protein LRRC8A is essential for swelling-activated Cl- currents and embryonic development in zebrafish". Physiological Reports. 4 (19): e12940. doi:10.14814/phy2.12940. PMC 5064130. PMID 27688432.
10. Okada T, Islam MR, Tsiferova NA, Okada Y, Sabirov RZ (March 2017). "Specific and essential but not sufficient roles of LRRC8A in the activity of volume-sensitive outwardly rectifying anion channel (VSOR)". Channels. 11 (2): 109–120. doi:10.1080/19336950.2016.1247133. PMC 5398601. PMID 27764579.
11. Lutter D, Ullrich F, Lueck JC, Kempa S, Jentsch TJ (March 2017). "Selective transport of neurotransmitters and modulators by distinct volume-regulated LRRC8 anion channels". Journal of Cell Science. 130 (6): 1122–1133. doi:10.1242/jcs.196253. PMID 28193731.
12. Planells-Cases R, Lutter D, Guyader C, Gerhards NM, Ullrich F, Elger DA, Kucukosmanoglu A, Xu G, Voss FK, Reincke SM, Stauber T, Blomen VA, Vis DJ, Wessels LF, Brummelkamp TR, Borst P, Rottenberg S, Jentsch TJ (December 2015). "Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs". The EMBO Journal. 34 (24): 2993–3008. doi:10.15252/embj.201592409. PMC 4687416. PMID 26530471.
13. Abascal, F; Zardoya, R (July 2012). "LRRC8 proteins share a common ancestor with pannexins, and may form hexameric channels involved in cell-cell communication". BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology. 34 (7): 551–60. doi:10.1002/bies.201100173. hdl:10261/124027. PMID 22532330. S2CID 24648128.
14. Deneka, D; Sawicka, M; Lam, AKM; Paulino, C; Dutzler, R (June 2018). "Structure of a volume-regulated anion channel of the LRRC8 family". Nature. 558 (7709): 254–259. Bibcode:2018Natur.558..254D. doi:10.1038/s41586-018-0134-y. PMID 29769723. S2CID 21696249.
15. Kefauver, JM; Saotome, K; Dubin, AE; Pallesen, J; Cottrell, CA; Cahalan, SM; Qiu, Z; Hong, G; Crowley, CS; Whitwam, T; Lee, WH; Ward, AB; Patapoutian, A (10 August 2018). "Structure of the human volume regulated anion channel". eLife. 7. doi:10.7554/eLife.38461. PMC 6086657. PMID 30095067.
16. Kasuya, G; Nakane, T; Yokoyama, T; Jia, Y; Inoue, M; Watanabe, K; Nakamura, R; Nishizawa, T; Kusakizako, T; Tsutsumi, A; Yanagisawa, H; Dohmae, N; Hattori, M; Ichijo, H; Yan, Z; Kikkawa, M; Shirouzu, M; Ishitani, R; Nureki, O (September 2018). "Cryo-EM structures of the human volume-regulated anion channel LRRC8". Nature Structural & Molecular Biology. 25 (9): 797–804. doi:10.1038/s41594-018-0109-6. PMID 30127360. S2CID 52047355.
17. Sawada A, Takihara Y, Kim JY, Matsuda-Hashii Y, Tokimasa S, Fujisaki H, Kubota K, Endo H, Onodera T, Ohta H, Ozono K, Hara J (December 2003). "A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans". The Journal of Clinical Investigation. 112 (11): 1707–13. doi:10.1172/JCI18937. PMC 281644. PMID 14660746.

Further reading

• Eggermont J, Trouet D, Carton I, Nilius B (2001). "Cellular function and control of volume-regulated anion channels". Cell Biochemistry and Biophysics. 35 (3): 263–74. doi:10.1385/CBB:35:3:263. PMID 11894846. S2CID 31821726.
• Mongin AA (March 2016). "Volume-regulated anion channel--a frenemy within the brain". Pflügers Archiv. 468 (3): 421–41. doi:10.1007/s00424-015-1765-6. PMC 4752865. PMID 26620797.
• Nagase T, Kikuno R, Ishikawa KI, Hirosawa M, Ohara O (February 2000). "Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 7 (1): 65–73. doi:10.1093/dnares/7.1.65. PMID 10718198.
• Kubota K, Kim JY, Sawada A, Tokimasa S, Fujisaki H, Matsuda-Hashii Y, Ozono K, Hara J (April 2004). "LRRC8 involved in B cell development belongs to a novel family of leucine-rich repeat proteins". FEBS Letters. 564 (1–2): 147–52. doi:10.1016/S0014-5793(04)00332-1. PMID 15094057. S2CID 29283213.
• Smits G, Kajava AV (July 2004). "LRRC8 extracellular domain is composed of 17 leucine-rich repeats". Molecular Immunology. 41 (5): 561–2. doi:10.1016/j.molimm.2004.04.001. PMID 15183935.
• Otsuki T, Ota T, Nishikawa T, Hayashi K, Suzuki Y, Yamamoto J, Wakamatsu A, Kimura K, Sakamoto K, Hatano N, Kawai Y, Ishii S, Saito K, Kojima S, Sugiyama T, Ono T, Okano K, Yoshikawa Y, Aotsuka S, Sasaki N, Hattori A, Okumura K, Nagai K, Sugano S, Isogai T (2007). "Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries". DNA Research. 12 (2): 117–26. doi:10.1093/dnares/12.2.117. PMID 16303743.
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (November 2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–48. doi:10.1016/j.cell.2006.09.026. PMID 17081983. S2CID 7827573.