LRRC8E explained

Leucine-rich repeat-containing protein 8E is a protein that in humans is encoded by the LRRC8E gene.^[1] Researchers have found out that this protein, along with the other LRRC8 proteins LRRC8A, LRRC8B, LRRC8C, and LRRC8D, 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 LRRC8E 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 LRRC8E, 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]

Specifically for LRRC8E, there has been a recent study that found that this gene was nominally associated with panic disorder.^[10]

Further reading

• Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S . The LIFEdb database in 2006 . Nucleic Acids Research . 34 . Database issue . D415–8 . January 2006 . 16381901 . 1347501 . 10.1093/nar/gkj139 .
• Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A . From ORFeome to biology: a functional genomics pipeline . Genome Research . 14 . 10B . 2136–44 . October 2004 . 15489336 . 528930 . 10.1101/gr.2576704 .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–95 . November 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• 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 .
• Hsu LY, Kim HJ, Sujansky E, Kousseff B, Hirschhorn K . Reciprocal translocation versus centric fusion between two No. 13 chromosomes. A case of 46,XX,-13,+t(13;13)(p12;q13) and a case of 46,XY,-13,+t(13;13)(p12;p12) . Cytogenetics and Cell Genetics . 12 . 4 . 235–44 . 2016 . 4752865 . 10.1007/s00424-015-1765-6 . 4752865 .
• 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 . 16–27 . October 2016 . 27688432 . 5064130 . 10.14814/phy2.12940 . [Change of inulin- and chloride-spaces during acute metabolic acidosis in the rat] .
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 . 10.15252/embj.201592409 . 4687416.
9. 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.
10. Gregersen NO, Buttenschøn HN, Hedemand A, Nielsen MN, Dahl HA, Kristensen AS, Johansen O, Woldbye DP, Erhardt A, Kruse TA, Wang AG, Børglum AD, Mors O . Association between genes on chromosome 19p13.2 and panic disorder . Psychiatric Genetics . 26 . 6 . 287–292 . December 2016 . 27610895 . 10.1097/YPG.0000000000000147 . 24158676 .