Woo, Dong Ho Han, Kyung-Seok Shim, Jae Wan Yoon, Bo-Eun Kim, Eunju Bae, Jin Young Oh, Soo-Jin Hwang, Eun Mi Marmorstein, Alan D. Bae, Yong Chul Park, Jae-Yong Lee, C. Justin 2024-01-20T14:02:45Z 2024-01-20T14:02:45Z 2021-09-05 2012-09 0092-8674 https://pubs.kist.re.kr/handle/201004/128901 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 G(alpha i), dissociation of G(beta gamma), and subsequent opening of glutamate-permeable, two-pore domain potassium channel TREK-1 through direct interaction between G(beta gamma) and N terminus of TREK-1. The slow mode is Ca2+ dependent and requires G(alpha q) 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 mu M, whereas slow mode targets neuronal NMDA receptors at around 1 mu M. Our results reveal two distinct sources of astrocytic glutamate that can differentially influence neighboring neurons. English Cell Press TREK-1 and Best1 Channels Mediate Fast and Slow Glutamate Release in Astrocytes upon GPCR Activation Article 10.1016/j.cell.2012.09.005 1 Cell, v.151, no.1, pp.25 - 40 Cell 151 1 25 40 N scie scopus 000309544200008 2-s2.0-84871863089 Biochemistry & Molecular Biology Cell Biology Biochemistry & Molecular Biology Cell Biology Article RAT HIPPOCAMPAL SLICES K+ CHANNELS SYNAPTIC-TRANSMISSION ANION CHANNEL RECEPTORS EXOCYTOSIS INHIBITION NEURONS CA2+ FREQUENCY