Biology:LRRC8C
 Generic protein structure example |
Leucine-rich repeat-containing protein 8C is a protein encoded by the human LRRC8C gene.[1]
Function
LRRC8C is one of five LRRC8 proteins—along with LRRC8A, LRRC8B, LRRC8D, and LRRC8E—that can form subunits of the heteromeric volume-regulated anion channel (VRAC).[2] These channels play a vital role in cell volume regulation by transporting chloride ions and organic osmolytes—including taurine and glutamate—across the plasma membrane.[3]
Although LRRC8C can contribute to VRAC composition, it appears to be less essential for VRAC activity than core subunits LRRC8A and LRRC8D.[4][5][6] However, studies have shown that LRRC8A and LRRC8D alone are not sufficient to support the full functional diversity of VRACs.[7] The presence of additional LRRC8 subunits, including LRRC8C, modulates substrate selectivity and functional properties of VRACs.[8][6]
Clinical significance
Recent findings suggest that LRRC8C may have more critical roles than previously recognized. A 2024 study identified monoallelic de novo variants in LRRC8C in two children with a severe congenital multisystem disorder (TIMES syndrome; see OMIM: https://omim.org/entry/621056).[9] These variants led to constitutive VRAC activation, resulting in channel hyperactivity and dysregulated ion transport, highlighting a pathogenic mechanism involving LRRC8C dysfunction.
Beyond its role in VRACs, the LRRC8 protein family has also been linked to agammaglobulinemia-5, a primary immunodeficiency disorder.[10]
References
- ↑ "Entrez Gene: LRRC8A leucine rich repeat containing 8 family, member A". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=56262.
- ↑ "Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC.". Science (New York, N.Y.) 344 (6184): 634–638. 2014-05-09. doi:10.1126/science.1252826. PMID 24790029. Bibcode: 2014Sci...344..634V. https://edoc.mdc-berlin.de/14008/1/14008oa.pdf.
- ↑ "VRACs and other ion channels and transporters in the regulation of cell volume and beyond". Nature Reviews. Molecular Cell Biology 17 (5): 293–307. 2016-05-17. doi:10.1038/nrm.2016.29. ISSN 1471-0072. PMID 27033257.
- ↑ "LRRC8A protein is indispensable for swelling-activated and ATP-induced release of excitatory amino acids in rat astrocytes.". The Journal of Physiology 592 (22): 4855–4862. 2014-11-15. doi:10.1113/jphysiol.2014.278887. PMID 25172945.
- ↑ "Leucine-rich repeat containing protein LRRC8A is essential for swelling-activated Cl− currents and embryonic development in zebrafish". Physiological Reports 4 (19). 2016-10-04. doi:10.14814/phy2.12940. PMID 27688432.
- ↑ 6.0 6.1 "Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs". The EMBO Journal 34 (24): 2993–3008. 2015-12-14. doi:10.15252/embj.201592409. PMID 26530471.
- ↑ "Specific and essential but not sufficient roles of LRRC8A in the activity of volume-sensitive outwardly rectifying anion channel (VSOR).". Channels (Austin, Tex.) 11 (2): 109–120. 2016-10-20. doi:10.1080/19336950.2016.1247133. PMID 27764579.
- ↑ "Selective transport of neurotransmitters and –modulators by distinct volume-regulated LRRC8 anion channels". Journal of Cell Science 130 (6): 1122–1133. 2017-03-15. doi:10.1242/jcs.196253. PMID 28193731.
- ↑ "De novo variants in LRRC8C resulting in constitutive channel activation cause a human multisystem disorder". The EMBO Journal 44 (2): 413–436. 2024. doi:10.1038/s44318-024-00322-y. PMID 39623139.
- ↑ "A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans.". The Journal of Clinical Investigation 112 (11): 1707–1713. December 2003. doi:10.1172/JCI18937. PMID 14660746.
Further reading
- "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. doi:10.1038/nrm.2016.29. PMID 27033257.
- "Cellular function and control of volume-regulated anion channels". Cell Biochemistry and Biophysics 35 (3): 263–274. 2001. doi:10.1385/CBB:35:3:263. PMID 11894846.
- "Volume-regulated anion channel – a frenemy within the brain". Pflügers Archiv: European Journal of Physiology 468 (3): 421–441. Mar 2016. doi:10.1007/s00424-015-1765-6. PMID 26620797.
- "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. Feb 2000. doi:10.1093/dnares/7.1.65. PMID 10718198.
- "A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans". The Journal of Clinical Investigation 112 (11): 1707–1713. Dec 2003. doi:10.1172/JCI18937. PMID 14660746.
- "LRRC8 involved in B cell development belongs to a novel family of leucine-rich repeat proteins". FEBS Letters 564 (1–2): 147–152. Apr 2004. doi:10.1016/S0014-5793(04)00332-1. PMID 15094057. Bibcode: 2004FEBSL.564..147K.
- "LRRC8 extracellular domain is composed of 17 leucine-rich repeats". Molecular Immunology 41 (5): 561–562. Jul 2004. doi:10.1016/j.molimm.2004.04.001. PMID 15183935.
- "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): 117–126. 2007. doi:10.1093/dnares/12.2.117. PMID 16303743.
- "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell 127 (3): 635–648. Nov 2006. doi:10.1016/j.cell.2006.09.026. PMID 17081983.
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