KMID : 0892920190280020183
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Experimental Neurobiology 2019 Volume.28 No. 2 p.183 ~ p.215
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Tweety-homolog (Ttyh) Family Encodes the Pore-forming Subunits of the Swelling-dependent Volume-regulated Anion Channel (VRACswell) in the Brain
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Han Young-Eun
Kwon Jea Won Joung-Ha An Hee-Young Jang Min-Woo Woo Jun-Sung Lee Je-Sun Park Min-Gu Yoon Bo-Eun Lee Seung-Eun Hwang Eun-Mi Jung Jae-Young Park Hyung-Ju Oh Soo-Jin Lee C. Justin
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Abstract
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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.
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KEYWORD
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Volume-regulated anion channel, VRAC, Tweety-homolog, Ttyh, Volume regulation
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