LRRC8C Membrane Protein Introduction

Introduction of LRRC8C

LRRC8C, also known as volume-regulated anion channel subunit LRRC8C or Leucine-rich repeat-containing protein 8C, is a protein encoded by the human LRRC8C gene. Volume-regulated anion channels (VRAC) are activated in response to hypotonic stress. These channels are composed of closely related paralogs of the leucine-rich repeat-containing protein 8 (LRRC8) family that co-assemble to form hexameric complexes. In mammals, this family includes five paralogs (LRRC8A-E), all of which have a high degree of sequence similarity. This protein consists of a transmembrane pore domain remotely associated with the pannexin protein, followed by a C-terminal domain containing 15-17 predicted leucine-rich repeats. The LRRC8 protein is widely expressed and forms heteromeric channels with different subunit and present different functional properties. Some components are selective for small anions, while other components can also penetrate amino acids and neurotransmitters, or participate in the uptake of antibiotics and anticancer drugs.

Function of LRRC8C Membrane Protein

The physiological function of VRAC as a cell volume regulator after permeation perturbation has been extensively studied in CNS neurons, assuming that VRAC plays an important role in neuronal volume regulation after activity-dependent swelling. Activation of VRAC under iso-volumetric conditions results in cell shrinkage, which has been demonstrated to be an important component in the process of apoptosis. VRAC activity is dependent on reactive oxygen species (ROS) and its activation is associated with increased ROS. ROS involves various physiological and pathophysiological conditions in all tissues. For instance, ROS is involved in the proliferation of cancer cells, playing an important role in the immune system. VRAC might also be important for angiogenesis as its blockers inhibit the formation of new blood vessel in several model systems. Another important role has been proposed in cell migration, which is inhibited by VRAC inhibitors in several cell types, presumably reflecting the close involvement of local cell volume changes in cell motility.

Fig.1 Part of the ESD of the LRRC8A/C model. Subunits A and C are shown in green and orange, respectively. (Deneka, 2018)

Application of LRRC8C Membrane Protein in Literature

1. Deneka D., et al. Structure of a volume-regulated anion channel of the LRRC8 family. Nature. 2018, 558(7709):254-259. PubMed ID: 29769723
   
   

   This article reveals the previously unknown architecture of volume-regulated anion channels and their mechanism of selective anion conduction.

2. Lutter D., et al. Selective transport of neurotransmitters and modulators by distinct volume-regulated LRRC8 anion channels. Journal of Cell Science. 2017, 130(6):1122-1133. PubMed ID: 28193731
   
   

   This paper indicates that a single VRAC can contain three or more different LRRC8 subunits and the composition-dependent effects of VRAC in extracellular signal transduction.

3. 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 article suggests that the stoichiometry of LRRC8 heteromers is variable, with a number of subunits ≥6, and that the heteromer composition depends on the relative expression of different subunits.

4. Mongin A.A. Volume-regulated anion channel-a frenemy within the brain. Pflügers Archiv-European Journal of Physiology. 2016, 468(3):421-41. PubMed ID: 26620797
   
   

   This review provides a brief overview of important findings from the central nervous system, with a focus on the expected impact of LRRC8 findings on the further development of neuroscience research.

5. Minieri L., et al. Intracellular Na(+) inhibits volume-regulated anion channel in rat cortical astrocytes. Journal of Neurochemistry. 2015, 132(3):286-300. PubMed ID: 25279950
   
   

   This article shows that intracellular Na(+) kinetics can regulate astrocytes membrane conductance, control functional processes associated with cell volume regulation, and further support the limitation of Na(+) accumulation in astrocytes may be a favorable strategy to counteract the development of brain edema.

LRRC8C Preparation Options

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Reference

1. Deneka D, et al. (2018). Structure of a volume-regulated anion channel of the LRRC8 family. Nature. 558(7709):254-259.

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