Tweety-homolog (Ttyh) Family Encodes the Pore-forming Subunits of the Swelling-dependent Volume-regulated Anion Channel (VRAC(swell)) in the Brain
- Authors
- Han, Young-Eun; Kwon, Jea; Won, Joungha; An, Heeyoung; Jang, Minwoo Wendy; Woo, Junsung; Lee, Je Sun; Park, Min Gu; Yoon, Bo-Eun; Lee, Seung Eun; Hwang, Eun Mi; Jung, Jae-Young; Park, Hyungju; Oh, Soo-Jin; Lee, C. Justin
- Issue Date
- Apr-2019
- Publisher
- KOREAN SOC BRAIN & NEURAL SCIENCE, KOREAN SOC NEURODEGENERATIVE DISEASE
- Keywords
- Volume -regulated anion channel; VRAC; Tweety-homolog; Ttyh; Volume regulation
- Citation
- EXPERIMENTAL NEUROBIOLOGY, v.28, no.2, pp.183 - 215
- Journal Title
- EXPERIMENTAL NEUROBIOLOGY
- Volume
- 28
- Number
- 2
- Start Page
- 183
- End Page
- 215
- URI
- http://scholarworks.bwise.kr/kbri/handle/2023.sw.kbri/694
- DOI
- 10.5607/en.2019.28.2.183
- ISSN
- 1226-2560
- 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 (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 Cl- conductance (I-Cl,I-swell) in cultured and hippocainpal astrocytes. When heterologously expressed in HEK293T or CHO-K1 cells, each TTYH iso-form showed a significant I-Cl,I-swell with similar aquaporin-4 dependency, pharmacological properties and glutamate permeability as I-Cl,I-swell observed in native astrocres. 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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