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 2024-01-19T20:31:22Z 2024-01-19T20:31:22Z 2021-09-02 2019-04 1226-2560 https://pubs.kist.re.kr/handle/201004/120176 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. English KOREAN SOC BRAIN & NEURAL SCIENCE, KOREAN SOC NEURODEGENERATIVE DISEASE SENSITIVE CL-CHANNEL CHLORIDE CURRENTS GLUTAMATE RELEASE ESSENTIAL COMPONENT ASTROCYTES ROLES PROTEIN IDENTIFICATION CONDUCTANCE EXPRESSION Tweety-homolog (Ttyh) Family Encodes the Pore-forming Subunits of the Swelling-dependent Volume-regulated Anion Channel (VRAC(swell)) in the Brain Article 10.5607/en.2019.28.2.183 1 EXPERIMENTAL NEUROBIOLOGY, v.28, no.2, pp.183 - 215 EXPERIMENTAL NEUROBIOLOGY 28 2 183 215 scie scopus kci ART002464026 000468151200006 2-s2.0-85066908958 Medicine, Research & Experimental Neurosciences Research & Experimental Medicine Neurosciences & Neurology Article SENSITIVE CL-CHANNEL CHLORIDE CURRENTS GLUTAMATE RELEASE ESSENTIAL COMPONENT ASTROCYTES ROLES PROTEIN IDENTIFICATION CONDUCTANCE EXPRESSION Volume -regulated anion channel VRAC Tweety-homolog Ttyh Volume regulation