Exp Neurobiol.
2019 Apr;28(2):183-215. 10.5607/en.2019.28.2.183.
Tweety-homolog (Ttyh) Family Encodes the Pore-forming Subunits of the Swelling-dependent Volume-regulated Anion Channel (VRAC(swell)) in the Brain
- Affiliations
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- 1Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, Korea. cjl@ibs.re.kr
- 2Department of Neuroscience, Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Korea.
- 3Center for Glia-Neuron Interaction, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.
- 4KU-KIST, Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Korea.
- 5Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.
- 6Molecular Neurobiology Laboratory, Dept. of Structure and Function of Neural Network, Korea Brain Research Institute, Daegu 41068, Korea.
- 7Department of molecular biology, Dankook University, Cheonan 31116, Korea.
- 8Virus Facility, Research Animal Resource Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.
- 9Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.
- KMID: 2450213
- DOI: http://doi.org/10.5607/en.2019.28.2.183
Abstract
- In the brain, a reduction in extracellular osmolality causes water-influx and swelling, which subsequently triggers Clâ»- and osmolytes-efflux via volume-regulated anion channel (VRAC). Although LRRC8 family has been recently proposed as the pore-forming VRAC which is activated by low cytoplasmic ionic strength but not by swelling, the molecular identity of the pore-forming swelling-dependent VRAC (VRAC(swell)) remains unclear. Here we identify and characterize Tweety-homologs (TTYH1, TTYH2, TTYH3) as the major VRAC(swell) in astrocytes. Gene-silencing of all Ttyh1/2/3 eliminated hypo-osmotic-solution-induced Clâ» conductance (I(Cl,swell)) in cultured and hippocampal astrocytes. When heterologously expressed in HEK293T or CHO-K1 cells, each TTYH isoform showed a significant I(Cl,swell) with similar aquaporin-4 dependency, pharmacological properties and glutamate permeability as I(Cl,swell) observed in native astrocytes. Mutagenesis-based structure-activity analysis revealed that positively charged arginine residue at 165 in TTYH1 and 164 in TTYH2 is critical for the formation of the channel-pore. Our results demonstrate that TTYH family confers the bona fide VRAC(swell) in the brain.
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