LRRC8D Membrane Protein Introduction

Introduction of LRRC8D

LRRC8D, also known as volume-regulated anion channel subunit LRRC8D or leucine-rich repeat-containing protein 8D, is a protein encoded by the human LRRC8D gene. The volume-regulated anion channel (VRAC) contains a heteromeric channel of the essential subunit LRRC8A and one or more other LRRC8 paralogs, which are widely expressed in vertebrate cells and mediate the swelling-induced release of Cl⁻ and organic solutes. VRAC is encoded by members of the leucine-rich repeats containing 8 (Lrrc8) gene family composed of a total of 5 members, respectively Lrrc8a-e. VRAC is an LRRC8 protein containing four predicted transmembrane domains and a cytoplasmic C-terminus. 15-17 leucine-rich motifs form a leucine-rich repeat (LRR) domain. The LRRC8A must be co-expressed with another family member to form the functional VRAC.

Function of LRRC8D Membrane Protein

Heteromeric LRRC8 channels (VRACs) can transport cisplatin and carboplatin, widely used in anti-cancer drugs, and the substrate selectivity and pharmacology of VRAC depend on its subunit composition. LRRC8D plays important pharmacological and physiological roles in supporting the transport of anti-cancer drugs and the organic osmolyte taurine. LRRC8 channels also facilitate drug-induced apoptosis independent of drug transport, revealing a dual role of VRAC in cisplatin toxicity. Activation of VRAC under equal volume conditions results in cell shrinkage and has been shown to be an important component of the process of apoptosis. VRAC may also be important for angiogenesis because its blockers inhibit the formation of new blood vessels in several model systems.

Fig.1 The VRAC consists of a mandatory LRRC8A subunit with an additional LRRC8B-E subunit. VRAC containing LRRC8D has a high permeability for the platinum anticancer drugs cisplatin and carboplatin, allowing the drug to enter cells and cause cell death. (Voets, 2016)

Application of LRRC8D Membrane Protein in Literature

1. Yamada T., et al. Intracellular and extracellular loops of LRRC8 are essential for volume-regulated anion channel function. Journal of general physiology. 2018, 150(7):1003-1015. PubMed ID: 29853476
   
   

   This paper demonstrates that LRRC8C, LRRC8D or LRRC8E, LRRC8A IL and EL1 are critical to the formation and function of VRAC and provides new insights into channel structure and regulation.

2. Gaitán-Peñas H., et al. Investigation of LRRC8-Mediated Volume-Regulated Anion Currents in Xenopus Oocytes. Biophysical Journal. 2016, 111(7):1429-1443. PubMed ID: 27705766
   
   

   This paper indicates that the stoichiometry of LRRC8 heteromers is variable, more than six subunits can be combined and the heteromer composition depends on the relative expression of different subunits.

3. Syeda R., et al. LRRC8 proteins form volume-regulated anion channels that sense ionic strength. Cell. 2016, 164(3):499-511. PubMed ID: 26824658
   
   

   This article demonstrates that LRRC8 protein is involved in the formation of VRAC pores, which can activate VRAC through a decrease in the cytoplasm.

4. Planells-Cases R., et al. Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs. Embo Journal. 2015, 34(24):2993-3008. PubMed ID:26530471
   
   

   This article suggests that VRAC containing LRRC8D is critical for organic osmotic pressure to regulate cell volume and may affect tumor cisplatin/carboplatin reactivity.

5. Lück J.C., et al. LRRC8/VRAC anion channels are required for late stages of spermatid development in mice. Journal of Biological Chemistry. 2018. PubMed ID: 29880644
   
   

   This article shows that VRAC may perform correct sperm development in a cell-autonomous manner through its role in cell volume regulation and explains the male infertility of Lrrc8a^-/- mice and the spontaneous mouse mutant ébouriffé.

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Reference

1. Voets T, et al. (2016). VRACs swallow platinum drugs. Embo Journal. 34(24):2985-2987.

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