Journal article
The volume-regulated anion channel (LRRC8) in nodose neurons is sensitive to acidic pH
JCI insight, Vol.2(5), pp.e90632-e90632
03/09/2017
DOI: 10.1172/jci.insight.90632
PMCID: PMC5333957
PMID: 28289711
Abstract
The leucine rich repeat containing protein 8A (LRRC8A), or SWELL1, is an essential component of the volume-regulated anion channel (VRAC) that is activated by cell swelling and ionic strength. We report here for the first time to our knowledge its expression in a primary cell culture of nodose ganglia neurons and its localization in the soma, neurites, and neuronal membrane. We show that this neuronal VRAC/SWELL1 senses low external pH (pH
o
) in addition to hypoosmolarity. A robust sustained chloride current is seen in 77% of isolated nodose neurons following brief exposures to extracellular acid pH. Its activation involves proton efflux, intracellular alkalinity, and an increase in NOX-derived H
2
O
2.
The molecular identity of both the hypoosmolarity-induced and acid pH
o
–conditioned VRAC as LRRC8A (SWELL1) was confirmed by Cre-flox–mediated KO, shRNA-mediated knockdown, and CRISPR/Cas9-mediated LRRC8A deletion in HEK cells and in primary nodose neuronal cultures. Activation of VRAC by low pH
o
reduces neuronal injury during simulated ischemia and N-methyl-D-aspartate–induced (NMDA-induced) apoptosis. These results identify the VRAC (LRRC8A) as a dual sensor of hypoosmolarity and low pH
o
in vagal afferent neurons and define the mechanisms of its activation and its neuroprotective potential.
Nodose neurons express the volume-regulated anion channel LRRC8A, which is activated by hypo-osmolarity and low pH.
Details
- Title: Subtitle
- The volume-regulated anion channel (LRRC8) in nodose neurons is sensitive to acidic pH
- Creators
- Runping Wang - Department of Internal MedicineYongjun Lu - Department of Internal MedicineSusheel Gunasekar - Department of Internal MedicineYanhui Zhang - Department of Internal MedicineChristopher J Benson - Department of Internal MedicineMark W Chapleau - Department of Internal MedicineRajan Sah - Department of Internal MedicineFrançois M Abboud - Department of Internal Medicine
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.2(5), pp.e90632-e90632
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/jci.insight.90632
- PMID
- 28289711
- PMCID
- PMC5333957
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Language
- English
- Date published
- 03/09/2017
- Academic Unit
- Molecular Physiology and Biophysics; Critical Care; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Nephrology; Neurosurgery; Internal Medicine
- Record Identifier
- 9984025352202771
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