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Lipopolysaccharide Induced Activation of VRAC (LRRC8) in Nodose Neurons Is Dependent on TLR4 Receptor Mediated ROS Generation
Author(s) -
Wang Runping,
Lu Yongjun,
Cicha Michael Z,
Chapleau Mark W,
Abboud Francois M
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb693
Subject(s) - chemistry , extracellular , reactive oxygen species , receptor , tlr4 , intracellular , microbiology and biotechnology , patch clamp , biochemistry , biology
The Volume‐Regulated Anion Channel and its essential subunit L eucine R ich R epeats C ontaining protein 8a (VRAC/LRRC8) is a widely expressed Cl − channel critical for cell volume regulation. This channel is activated by osmotic gradient and ionic strength (Voss et al., 2014, Qiu et al., 2014, Syeda et al., 2016). Using patch‐clamp techniques, we reported that channel activation is also induced in the majority of vagal afferent neurons isolated from mouse (C57BL/6) nodose ganglia by hypoosmolarity and by extracellular low pH (Wang et al., 2017). We have also observed that this current is activated by lipopolysaccharide (LPS) at 10μg/ml. Here we tested the hypothesis that the response to LPS is dependent on toll‐like receptor 4 (TLR4) and is mediated by intracellular reactive oxygen species (ROS). The current was reduced from 26.7±5.4 pA/pF (n=5) in control peptide‐treated neurons to 6.4±2.1 pA/pF (n=6, p<0.05) in neurons treated with the TLR4 inhibitor peptide VIPER. Application of LPS at a lower dose (100ng/ml) increased intracellular neuronal ROS measured by dihydroethidium within several minutes. The cell permeable hydrogen peroxide scavenger PEG‐catalase decreased the LPS‐induced current from 10.2±2.5 pA/pF (n=7) to 2.3±1.2 pA/pF (n=5, p<0.05). We conclude that LPS induces activation of the VRAC/LRRC8 channel in nodose neurons via TLR4 receptor‐mediated ROS generation. The results indicate a diverse functional role of this channel beyond volume homeostasis with potential implications in high fat diet‐ or LPS‐induced decrease in satiety signaling in intestinal vagal afferents. Support or Funding Information HL14388