LRRC8A explained

Leucine-rich repeat-containing protein 8A is a protein that in humans is encoded by the LRRC8A gene.^[1] 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).^[2] 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,^[3] and that is not the only function these channels have been linked to.

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.^{[4] [5]} 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.^[6] This is where the other LRRC8 proteins come in, as the different composition of these subunits affects the range of specificity for VRACs.^{[7] [8]}

The transmembrane portion of LRRC8 proteins are similar to those in Pannexins.^[9] LRRC8A alone can form a hexameric VRAC, for which the cyro-EM structure has been determined in its mice and human versions.^{[10] [11] [12]}

In addition to its role in VRACs, the LRRC8 protein family is also associated with agammaglobulinemia-5.^[13]

Further reading

• Eggermont J, Trouet D, Carton I, Nilius B . Cellular function and control of volume-regulated anion channels . . 35 . 3 . 263–74 . 2001 . 11894846 . 10.1385/CBB:35:3:263 . 31821726 .
• Mongin AA . Volume-regulated anion channel--a frenemy within the brain . Pflügers Archiv . 468 . 3 . 421–41 . March 2016 . 26620797 . 4752865 . 10.1007/s00424-015-1765-6 .
• Nagase T, Kikuno R, Ishikawa KI, Hirosawa M, Ohara O . 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 . February 2000 . 10718198 . 10.1093/dnares/7.1.65 . free .
• Kubota K, Kim JY, Sawada A, Tokimasa S, Fujisaki H, Matsuda-Hashii Y, Ozono K, Hara J . LRRC8 involved in B cell development belongs to a novel family of leucine-rich repeat proteins . FEBS Letters . 564 . 1–2 . 147–52 . April 2004 . 15094057 . 10.1016/S0014-5793(04)00332-1 . 29283213 .
• Smits G, Kajava AV . LRRC8 extracellular domain is composed of 17 leucine-rich repeats . Molecular Immunology . 41 . 5 . 561–2 . July 2004 . 15183935 . 10.1016/j.molimm.2004.04.001 .
• 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 . 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 . 2007 . 16303743 . 10.1093/dnares/12.2.117 . free .
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks . Cell . 127 . 3 . 635–48 . November 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . 7827573 . free .

Notes and References

1. Web site: Entrez Gene: LRRC8A leucine rich repeat containing 8 family, member A.
2. Voss FK, Ullrich F, Münch J, Lazarow K, Lutter D, Mah N, Andrade-Navarro MA, von Kries JP, Stauber T, Jentsch TJ . Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC . Science . 344 . 6184 . 634–8 . May 2014 . 24790029 . 10.1126/science.1252826 . 2014Sci...344..634V . 24709412 .
3. Jentsch TJ . VRACs and other ion channels and transporters in the regulation of cell volume and beyond . Nature Reviews Molecular Cell Biology . 17 . 5 . 293–307 . May 2016 . 27033257 . 10.1038/nrm.2016.29 . 40565653 .
4. Hyzinski-García MC, Rudkouskaya A, Mongin AA . 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 . November 2014 . 25172945 . 4259531 . 10.1113/jphysiol.2014.278887 .
5. Yamada T, Wondergem R, Morrison R, Yin VP, Strange K . Leucine-rich repeat containing protein LRRC8A is essential for swelling-activated Cl- currents and embryonic development in zebrafish . Physiological Reports . 4 . 19 . October 2016 . 27688432 . 5064130 . 10.14814/phy2.12940 . e12940.
6. Okada T, Islam MR, Tsiferova NA, Okada Y, Sabirov RZ . 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 . March 2017 . 27764579 . 10.1080/19336950.2016.1247133 . 5398601.
7. Lutter D, Ullrich F, Lueck JC, Kempa S, Jentsch TJ . Selective transport of neurotransmitters and modulators by distinct volume-regulated LRRC8 anion channels . Journal of Cell Science . 130 . 6 . 1122–1133 . March 2017 . 28193731 . 10.1242/jcs.196253 . free .
8. 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 . Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs . The EMBO Journal . 34 . 24 . 2993–3008 . December 2015 . 26530471 . 4687416 . 10.15252/embj.201592409 .
9. Abascal . F . Zardoya . R . LRRC8 proteins share a common ancestor with pannexins, and may form hexameric channels involved in cell-cell communication. . BioEssays . July 2012 . 34 . 7 . 551–60 . 10.1002/bies.201100173 . 22532330. 10261/124027 . 24648128 . free .
10. Deneka . D . Sawicka . M . Lam . AKM . Paulino . C . Dutzler . R . Structure of a volume-regulated anion channel of the LRRC8 family. . Nature . June 2018 . 558 . 7709 . 254–259 . 10.1038/s41586-018-0134-y . 29769723. 2018Natur.558..254D . 21696249 .
11. 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 . Structure of the human volume regulated anion channel. . eLife . 10 August 2018 . 7 . 10.7554/eLife.38461 . 30095067. 6086657 . free .
12. 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 . Cryo-EM structures of the human volume-regulated anion channel LRRC8. . Nature Structural & Molecular Biology . September 2018 . 25 . 9 . 797–804 . 10.1038/s41594-018-0109-6 . 30127360. 52047355 .
13. 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 . A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans . The Journal of Clinical Investigation . 112 . 11 . 1707–13 . December 2003 . 14660746 . 10.1172/JCI18937 . 281644.