2. Academic Validation
  3. Tweety-homolog (Ttyh) Family Encodes the Pore-forming Subunits of the Swelling-dependent Volume-regulated Anion Channel (VRACswell) in the Brain

Tweety-homolog (Ttyh) Family Encodes the Pore-forming Subunits of the Swelling-dependent Volume-regulated Anion Channel (VRACswell) in the Brain

  • Exp Neurobiol. 2019 Apr;28(2):183-215. doi: 10.5607/en.2019.28.2.183.
Young-Eun Han 1 2 3,  Jea Kwon 1 3 4,  Joungha Won 1 3 5,  Heeyoung An 1 3 4,  Minwoo Wendy Jang 1 3 4,  Junsung Woo 3,  Je Sun Lee 6,  Min Gu Park 1 3 4,  Bo-Eun Yoon 7,  Seung Eun Lee 8,  Eun Mi Hwang 3,  Jae-Young Jung 2 3,  Hyungju Park 6,  Soo-Jin Oh 3 9,  C Justin Lee 1 2 3
Affiliations

Affiliations

  • 1 Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, Korea.
  • 2 Department of Neuroscience, Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Korea.
  • 3 Center for Glia-Neuron Interaction, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.
  • 4 KU-KIST, Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Korea.
  • 5 Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.
  • 6 Molecular Neurobiology Laboratory, Dept. of Structure and Function of Neural Network, Korea Brain Research Institute, Daegu 41068, Korea.
  • 7 Department of molecular biology, Dankook University, Cheonan 31116, Korea.
  • 8 Virus Facility, Research Animal Resource Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.
  • 9 Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.
PMID: 31138989 DOI: 10.5607/en.2019.28.2.183
Abstract

In the brain, a reduction in extracellular osmolality causes water-influx and swelling, which subsequently triggers Cl-- 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 (VRACswell) remains unclear. Here we identify and characterize Tweety-homologs (TTYH1, TTYH2, TTYH3) as the major VRACswell in astrocytes. Gene-silencing of all Ttyh1/2/3 eliminated hypo-osmotic-solution-induced Cl- conductance (ICl,swell) in cultured and hippocampal astrocytes. When heterologously expressed in HEK293T or CHO-K1 cells, each TTYH isoform showed a significant ICl,swell with similar aquaporin-4 dependency, pharmacological properties and glutamate permeability as ICl,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 VRACswell in the brain.

Keywords

Ttyh; Tweety-homolog; VRAC; Volume regulation; Volume-regulated anion channel.

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