LRRC8D explained

Leucine-rich repeat-containing protein 8D is a protein that in humans is encoded by the LRRC8D gene.^[1] Researchers have found out that this protein, along with the other LRRC8 proteins LRRC8A, LRRC8B, LRRC8C, and LRRC8E, is 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 LRRC8D is one of many proteins that can be part of VRAC, it is in fact one of the most important subunits for the channel’s ability to function; the other protein of importance is LRRC8A.^{[4] [5]} However, while we know it is necessary for specific 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]}

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

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 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA . A "double adaptor" method for improved shotgun library construction . Analytical Biochemistry . 236 . 1 . 107–13 . April 1996 . 8619474 . 10.1006/abio.1996.0138 .
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA . Large-scale concatenation cDNA sequencing . Genome Research . 7 . 4 . 353–8 . April 1997 . 9110174 . 139146 . 10.1101/gr.7.4.353 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Lehner B, Sanderson CM . A protein interaction framework for human mRNA degradation . Genome Research . 14 . 7 . 1315–23 . July 2004 . 15231747 . 442147 . 10.1101/gr.2122004 .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
• 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 . free .
• 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. 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.