LRRC8B Membrane Protein Introduction

Introduction of LRRC8B

LRRC8B, also known as volume-regulated anion channel subunit LRRC8B or Leucine-rich repeat-containing protein 8B, is a protein encoded by the human LRRC8B gene. The volume-regulated anion channel (VRAC), also known as volume-sensitive outwardly rectifying anion channel (VSOR) or volume-sensitive organic osmolyte and anion channel (VSOAC), is ubiquitously expressed in vertebrate cells. VRAC is discovered to be constituted of LRRC8 heteromers that are formed by the obligatory subunit LRRC8A and at least one other member of the LRRC8 protein family (LRRC8 B-E). LRRC8 proteins have four transmembrane helices followed by a long cytoplasmic tail that contains many leucine-rich repeats. Based on their similarity to pannexins and connexins, LRRC8 proteins are believed to assemble to hexameric channels which are recently confirmed by cryo-EM structures. Depending on the LRRC8 subunit composition, VRACs can also conduct a wide range of organic compounds.

Function of LRRC8B Membrane Protein

The physiological function of VRAC as a cell volume regulator after osmotic pressure has been extensively studied in CNS neurons, where VRAC is thought to play an important role in neuronal volume regulation after activity-dependent swelling. An important pathophysiological correlation is that when astrocytes expand in large numbers after ischemic injury, they can release large amounts of glutamate through VRAC, leading to excitatory neuronal death. In addition to this, VRAC has a wide range of additional physiological functions, such as participation in apoptosis and angiogenesis, because its blockers can inhibit the formation of new blood vessels in several model systems. Besides, the LRRC8 heteromeric channel is strongly regulated by oxidation. It is documented that the LRRC8A/8E heteromeric channel is significantly enhanced by oxidation, while the LRRC8A/8C and LRRC8A/8D heteromeric channels are blocked.

Fig.1 Cartoon showing key structural features of LRRC8 protein. LRRC8 proteins comprise four predicted transmembrane domains (TMDs), a large EL1 connecting TMDs 1 and 2, an IL connecting TMDs 2 and 3, and a C-terminal LRR domain. (Yamada, 2018)

Application of LRRC8B Membrane Protein in Literature

1. Pedersen S.F., et al. The identification of a volume-regulated anion channel: an amazing Odyssey. Acta Physiologica. 2015, 213(4):868-81. PubMed ID: 25565132
   
   

   This article describes the properties of LRRC8 protein, highlights some characteristics of LRRC8A knockout mice, and discusses the impact of LRRC8 as a VRAC discovery in future research.

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 article suggests that an individual VRAC may contain three or more different LRRC8 subunits, which is evidenced by sequential co-immunoprecipitation and the compositional dependence of VRAC in extracellular signal transduction.

3. Wang R., et al. The volume-regulated anion channel (LRRC8) in nodose neurons is sensitive to acidic pH. Jci Insight. 2017, 2(5):e90632. PubMed ID:28791474
   
   

   This article shows that the VRAC (LRRC8A) is used as a dual sensor for low osmotic pressure and low pH in vagal afferent neurons, and its activation mechanism and neuroprotective potential are determined.

4. Gradogna A., et al. Subunit dependent oxidative stress sensitivity of LRRC8 volume regulated anion channels. Journal of Physiology. 2017, 595(21):6719-6733. PubMed ID: 28841766
   
   

   This article indicates that the LRRC8 channel is directly regulated by oxidation in a sub-dependent manner.

5. JVoss F.K., et al. Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC. Science. 2014, 344(6184):634-8. PubMed ID: 24790029
   
   

   This paper shows that VRAC is identical to the volume-sensitive organic permeate/anion channel VSOAC and explains the heterogeneity of the native VRAC current.

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Reference

1. Yamada T and Strange K. (2018). Intracellular and extracellular loops of LRRC8 are essential for volume-regulated anion channel function. Journal of general physiology. 150(7):1003-1015.

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