@article{5203d24a3ce846bd8fe22dabfcefd71b,
title = "TREK-1 and Best1 Channels Mediate Fast and Slow Glutamate Release in Astrocytes upon GPCR Activation",
abstract = "Astrocytes release glutamate upon activation of various GPCRs to exert important roles in synaptic functions. However, the molecular mechanism of release has been controversial. Here, we report two kinetically distinct modes of nonvesicular, channel-mediated glutamate release. The fast mode requires activation of Gαi, dissociation of Gβγ, and subsequent opening of glutamate-permeable, two-pore domain potassium channel TREK-1 through direct interaction between Gβγ and N terminus of TREK-1. The slow mode is Ca2+ dependent and requires Gαq activation and opening of glutamate-permeable, Ca2+-activated anion channel Best1. Ultrastructural analyses demonstrate that TREK-1 is preferentially localized at cell body and processes, whereas Best1 is mostly found in microdomains of astrocytes near synapses. Diffusion modeling predicts that the fast mode can target neuronal mGluR with peak glutamate concentration of 100 μM, whereas slow mode targets neuronal NMDA receptors at around 1 μM. Our results reveal two distinct sources of astrocytic glutamate that can differentially influence neighboring neurons.",
author = "Woo, {Dong Ho} and Han, {Kyung Seok} and Shim, {Jae Wan} and Yoon, {Bo Eun} and Eunju Kim and Bae, {Jin Young} and Oh, {Soo Jin} and Hwang, {Eun Mi} and Marmorstein, {Alan D.} and Bae, {Yong Chul} and Park, {Jae Yong} and Lee, {C. Justin}",
note = "Funding Information: This work was supported by the World Class Institute (WCI 2009-003), MRC (2012-0000305), and Basic Science Research (2010-0029460) Programs of the NRF funded by the MEST of Korea and also by NIH (R01-EY013160) and a grant from Research to Prevent Blindness to the Department of Ophthalmology and Vision Science at the University of Arizona. We thank George Augustine, Larry Cohen, and Keiko Tanaka for careful editing of the manuscript. We thank Taekeun Kim for technical support for immunocytochemistry, Nammi Park for technical support for Y2H, Lucie Langevin for providing clone of pRK-β-Ark-C terminus, and Nevin A. Lambert for pCDNA3.1-SS-ECFP-TM-Gi1-CG (GiCG) and pCDNA3.1-SS-ECFP-TM-Gs. Funding Information: This work was supported by the World Class Institute (WCI 2009-003), MRC (2012-0000305), and Basic Science Research (2010-0029460) Programs of the NRF funded by the MEST of Korea and also by NIH (R01-EY013160) and a grant from Research to Prevent Blindness to the Department of Ophthalmology and Vision Science at the University of Arizona. We thank George Augustine, Larry Cohen, and Keiko Tanaka for careful editing of the manuscript. We thank Taekeun Kim for technical support for immunocytochemistry, Nammi Park for technical support for Y2H, Lucie Langevin for providing clone of pRK-β-Ark-C terminus, and Nevin A. Lambert for pCDNA3.1-SS-ECFP-TM-Gi1-CG (GiCG) and pCDNA3.1-SS-ECFP-TM-Gs. Publisher Copyright: {\textcopyright} 2012 Elsevier Inc.",
year = "2012",
month = sep,
day = "28",
doi = "10.1016/j.cell.2012.09.005",
language = "English (US)",
volume = "151",
pages = "25--40",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "1",
}