VRAC: Molecular Identification As LRRC8 Heteromers with Differential Functions

Overview

Journal Pflugers Arch

Specialty Physiology

Date 2015 Dec 5

PMID 26635246

Citations 47

Authors

Thomas J Jentsch

Darius Lutter

Rosa Planells-Cases

Florian Ullrich

Felizia K Voss

Affiliations

Soon will be listed here.

Abstract

A major player of vertebrate cell volume regulation is the volume-regulated anion channel (VRAC), which conducts halide ions and organic osmolytes to counteract osmotic imbalances. The molecular entity of this channel was unknown until very recently, although its biophysical characteristics and diverse physiological roles have been extensively studied over the last 30 years. On the road to the molecular identification of VRAC, experimental difficulties led to the proposal of a variety of false candidates. In 2014, in a final breakthrough, two groups independently identified LRRC8A as indispensable component of VRAC. LRRC8A is part of the leucine-rich repeat containing 8 family, which is comprised of five members (LRRC8A-E). Of those, LRRC8A is an obligatory subunit of VRAC but it needs at least one of the other family members to mediate the swelling-induced Cl(-) current ICl,vol. This review discusses the remarkable journey which led to the molecular identification of VRAC, evidence for LRRC8 proteins forming the VRAC pore and their heteromeric assembly. Furthermore, first major insights on the role of LRRC8 proteins in cancer drug resistance and apoptosis and the role of LRRC8D in cisplatin and taurine transport will be summarized.

Citing Articles

Volume-regulated anion channels conduct ATP in undifferentiated mammary cells and promote tumorigenesis in xenograft nude mouse.

Furuya K, Hirata H, Kobayashi T, Ishiguro H, Sokabe M Front Cell Dev Biol. 2025; 12:1519642.

PMID: 39882260 PMC: 11774906. DOI: 10.3389/fcell.2024.1519642.

Downregulation of IL-8 and IL-10 by LRRC8A Inhibition through the NOX2-Nrf2-CEBPB Transcriptional Axis in THP-1-Derived M Macrophages.

Matsui M, Kajikuri J, Kito H, Elboray E, Suzuki T, Ohya S Int J Mol Sci. 2024; 25(17).

PMID: 39273558 PMC: 11395230. DOI: 10.3390/ijms25179612.

Comprehensive review on the novel immunotherapy target: Leucine-rich repeat-containing 8A/volume-regulated anion channel.

Hu Y, Qin J, Ma Y, Yang R, Liu X, Shi C Int J Biol Sci. 2024; 20(10):3881-3891.

PMID: 39113714 PMC: 11302880. DOI: 10.7150/ijbs.95933.

Interactomic exploration of LRRC8A in volume-regulated anion channels.

Carpanese V, Festa M, Prosdocimi E, Bachmann M, Sadeghi S, Bertelli S Cell Death Discov. 2024; 10(1):299.

PMID: 38909013 PMC: 11193767. DOI: 10.1038/s41420-024-02032-0.

Targeting ferroptosis as a potential strategy to overcome the resistance of cisplatin in oral squamous cell carcinoma.

Chen R, Zhu S, Zhao R, Liu W, Jin L, Ren X Front Pharmacol. 2024; 15:1402514.

PMID: 38711989 PMC: 11071065. DOI: 10.3389/fphar.2024.1402514.

References

Shimizu T, Lee E, Ise T, Okada Y . Volume-sensitive Cl(-) channel as a regulator of acquired cisplatin resistance. Anticancer Res. 2008; 28(1A):75-83. View

Lee C, Freinkman E, Sabatini D, Ploegh H . The protein synthesis inhibitor blasticidin s enters mammalian cells via leucine-rich repeat-containing protein 8D. J Biol Chem. 2014; 289(24):17124-31. PMC: 4059153. DOI: 10.1074/jbc.M114.571257. View

Kumar L, Chou J, Yee C, Borzutzky A, Vollmann E, von Andrian U . Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function. J Exp Med. 2014; 211(5):929-42. PMC: 4010910. DOI: 10.1084/jem.20131379. View

Shimizu T, Numata T, Okada Y . A role of reactive oxygen species in apoptotic activation of volume-sensitive Cl(-) channel. Proc Natl Acad Sci U S A. 2004; 101(17):6770-3. PMC: 404120. DOI: 10.1073/pnas.0401604101. View

Hyzinski-Garcia M, Rudkouskaya A, Mongin A . LRRC8A protein is indispensable for swelling-activated and ATP-induced release of excitatory amino acids in rat astrocytes. J Physiol. 2014; 592(22):4855-62. PMC: 4259531. DOI: 10.1113/jphysiol.2014.278887. View

Grinstein S, Clarke C, Dupre A, Rothstein A . Volume-induced increase of anion permeability in human lymphocytes. J Gen Physiol. 1982; 80(6):801-23. PMC: 2228648. DOI: 10.1085/jgp.80.6.801. View

Qiu Z, Dubin A, Mathur J, Tu B, Reddy K, Miraglia L . SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel. Cell. 2014; 157(2):447-458. PMC: 4023864. DOI: 10.1016/j.cell.2014.03.024. View

Gay N, Symmons M, Gangloff M, Bryant C . Assembly and localization of Toll-like receptor signalling complexes. Nat Rev Immunol. 2014; 14(8):546-58. DOI: 10.1038/nri3713. View

Jackson P, Strange K . Volume-sensitive anion channels mediate swelling-activated inositol and taurine efflux. Am J Physiol. 1993; 265(6 Pt 1):C1489-500. DOI: 10.1152/ajpcell.1993.265.6.C1489. View

10.

Schroeder B, Cheng T, Jan Y, Jan L . Expression cloning of TMEM16A as a calcium-activated chloride channel subunit. Cell. 2008; 134(6):1019-29. PMC: 2651354. DOI: 10.1016/j.cell.2008.09.003. View

11.

Shennan D . Swelling-induced taurine transport: relationship with chloride channels, anion-exchangers and other swelling-activated transport pathways. Cell Physiol Biochem. 2008; 21(1-3):15-28. DOI: 10.1159/000113743. View

12.

Juul C, Grubb S, Poulsen K, Kyed T, Hashem N, Lambert I . Anoctamin 6 differs from VRAC and VSOAC but is involved in apoptosis and supports volume regulation in the presence of Ca2+. Pflugers Arch. 2014; 466(10):1899-910. PMC: 4159566. DOI: 10.1007/s00424-013-1428-4. View

13.

Voss F, Ullrich F, Munch J, Lazarow K, Lutter D, Mah N . Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC. Science. 2014; 344(6184):634-8. DOI: 10.1126/science.1252826. View

14.

Grenningloh G, Rienitz A, Schmitt B, Methfessel C, Zensen M, Beyreuther K . The strychnine-binding subunit of the glycine receptor shows homology with nicotinic acetylcholine receptors. Nature. 1987; 328(6127):215-20. DOI: 10.1038/328215a0. View

15.

Banderali U, Roy G . Anion channels for amino acids in MDCK cells. Am J Physiol. 1992; 263(6 Pt 1):C1200-7. DOI: 10.1152/ajpcell.1992.263.6.C1200. View

16.

Ise T, Shimizu T, Lee E, Inoue H, Kohno K, Okada Y . Roles of volume-sensitive Cl- channel in cisplatin-induced apoptosis in human epidermoid cancer cells. J Membr Biol. 2005; 205(3):139-45. DOI: 10.1007/s00232-005-0779-y. View

17.

Nilius B, Sehrer J, Viana F, de Greef C, Raeymaekers L, Eggermont J . Volume-activated Cl- currents in different mammalian non-excitable cell types. Pflugers Arch. 1994; 428(3-4):364-71. DOI: 10.1007/BF00724520. View

18.

Frech G, VanDongen A, Schuster G, Brown A, Joho R . A novel potassium channel with delayed rectifier properties isolated from rat brain by expression cloning. Nature. 1989; 340(6235):642-5. DOI: 10.1038/340642a0. View

19.

Hazama A, Okada Y . Ca2+ sensitivity of volume-regulatory K+ and Cl- channels in cultured human epithelial cells. J Physiol. 1988; 402:687-702. PMC: 1191916. DOI: 10.1113/jphysiol.1988.sp017229. View

20.

Pedersen S, Klausen T, Nilius B . The identification of a volume-regulated anion channel: an amazing Odyssey. Acta Physiol (Oxf). 2015; 213(4):868-81. DOI: 10.1111/apha.12450. View