LRRC8C explained

Leucine-rich repeat-containing protein 8C is a protein that in humans is encoded by the LRRC8C gene.^[1] Researchers have found out that this protein, along with the other LRRC8 proteins LRRC8A, LRRC8B, LRRC8D, and LRRC8E, is sometimes a subunit of the heteromer protein Volume-Regulated Anion Channel.^[2] Volume-Regulated Anion Channels (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 LRRC8C is one of many proteins that can be part of VRAC, research has found that it is not as crucial to the activity of the channel in comparison to LRRC8A and LRRC8D.^{[4] [5]} However, while we know that LRRC8A and LRRC8D are necessary for VRAC function, other studies have found that they are not sufficient for the full range of usual VRAC activity.^[6] This is where the other LRRC8 proteins come in, such as LRRC8C, as the different composition of these subunits affects the range of specificity for VRACs.^{[7] [8]}

In addition to its role in VRACs, the LRRC8 protein family is also associated with agammaglobulinemia-5.^[9]

Further reading

• Jentsch Thomas J . VRACs and other ion channels and transporters in the regulation of cell volume and beyond . Nature Reviews Molecular Cell Biology . 17 . 2 . 293–307 . 2016 . 27033257 . 10.1038/nrm.2016.29. 40565653 .
• Eggermont D, Trouet I, Carton I, etal . Cellular function and control of volume-regulated anion channels . . 35 . 3 . 263–74 . 2001 . 11894846. 10.1385/CBB:35:3:263 . 31821726 .
• Mongin Alexander. Volume-regulated anion channel – a frenemy within the brain . Pflügers Archiv . 468 . 3 . 421–441 . 2016 . 4752865 . 10.1007/s00424-015-1765-6. 26620797 .
• Nagase T, Kikuno R, Ishikawa KI, etal . 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 Res. . 7 . 1 . 65–73 . 2000 . 10718198 . 10.1093/dnares/7.1.65 . free .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Clark HF, Gurney AL, Abaya E, etal . The Secreted Protein Discovery Initiative (SPDI), a Large-Scale Effort to Identify Novel Human Secreted and Transmembrane Proteins: A Bioinformatics Assessment . Genome Res. . 13 . 10 . 2265–70 . 2003 . 12975309 . 10.1101/gr.1293003 . 403697 .
• Sawada A, Takihara Y, Kim JY, etal . A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans . J. Clin. Invest. . 112 . 11 . 1707–13 . 2004 . 14660746 . 10.1172/JCI18937 . 281644 .
• Ota T, Suzuki Y, Nishikawa T, etal . Complete sequencing and characterization of 21,243 full-length human cDNAs . Nat. Genet. . 36 . 1 . 40–5 . 2004 . 14702039 . 10.1038/ng1285 . free .
• Kubota K, Kim JY, Sawada A, etal . LRRC8 involved in B cell development belongs to a novel family of leucine-rich repeat proteins . FEBS Lett. . 564 . 1–2 . 147–52 . 2004 . 15094057 . 10.1016/S0014-5793(04)00332-1 .
• Humphray SJ, Oliver K, Hunt AR, etal . DNA sequence and analysis of human chromosome 9 . Nature . 429 . 6990 . 369–74 . 2004 . 15164053 . 10.1038/nature02465 . 2734081 . 2004Natur.429..369H .
• Smits G, Kajava AV . LRRC8 extracellular domain is composed of 17 leucine-rich repeats . Mol. Immunol. . 41 . 5 . 561–2 . 2004 . 15183935 . 10.1016/j.molimm.2004.04.001 .
• Gerhard DS, Wagner L, Feingold EA, etal . The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC) . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 .
• Otsuki T, Ota T, Nishikawa T, etal . 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 Res. . 12 . 2 . 117–26 . 2007 . 16303743 . 10.1093/dnares/12.2.117 . free .
• Olsen JV, Blagoev B, Gnad F, etal . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks . Cell . 127 . 3 . 635–48 . 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. Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC.. Science . 2014-05-09 . 344 . 6184 . 634–8 . 10.1126/science.1252826 . Felizia . Voss . Florian . Ullrich . Jonas . Münch. 24790029. Submitted manuscript . 2014Sci...344..634V . 24709412 .
3. VRACs and other ion channels and transporters in the regulation of cell volume and beyond . Nature Reviews Molecular Cell Biology . 2016-05-17 . 1471-0072 . 27033257 . 293–3017 . 17 . 2 . 10.1038/nrm.2016.29 . Thomas J. . Jentsch . 40565653 .
4. LRRC8A protein is indispensable for swelling-activated and ATP-induced release of excitatory amino acids in rat astrocytes. . 25172945. The Journal of Physiology . 592. 22. 4855–62. 2014-11-15 . 4259531 . 10.1113/jphysiol.2014.278887 . María C . Hyzinski-García . Alena . Rudkouskaya . Alexander . Mongin.
5. Leucine-rich repeat containing protein LRRC8A is essential for swelling-activated Cl⁻ currents and embryonic development in zebrafish. 27688432 . Physiological Reports. 4 . 19 . e12940 . 2016-10-04 . 5064130 . 10.14814/phy2.12940 . Toshiki . Yamada . Robert . Wondergem . Rebecca . Morrison.
6. 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 . 2016-10-20 . 27764579 . 5398601 . 10.1080/19336950.2016.1247133 . T . Okada . MR . Islam . NA . Tsiferova.
7. Selective transport of neurotransmitters and –modulators by distinct volume-regulated LRRC8 anion channels. Journal of Cell Science. 130 . 6 . 1122–1133 . 2017-03-15 . 28193731 . 10.1242/jcs.196253. D . Lutter . F . Ullrich . JC . Lueck. free .
8. Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs . EMBO Journal . 2015-12-14 . 34 . 24 . 2993–3008 . 10.15252/embj.201592409 . 26530471 . Rosa . Planells-Cases . Darius . Lutter . Charlotte . Guyader. 4687416.
9. A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans. . Journal of Clinical Investigation. 112 . 11 . 1707–13 . December 2003 . 10.1172/JCI18937 . A . Sawada . Y . Takihara . JY . Kim. 14660746 . 281644 .