TREK-1 and Best1 channels mediate fast and slow glutamate release in astrocytes upon GPCR activation.

Dong Ho Woo, Kyung Seok Han, Jae Wan Shim, Bo Eun Yoon, Eunju Kim, Jin Young Bae, Soo Jin Oh, Eun Mi Hwang, Alan D. Marmorstein, Yong Chul Bae, Jae Yong Park, C. Justin Lee

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165 Citations (Scopus)

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 G(αi), dissociation of G(βγ), and subsequent opening of glutamate-permeable, two-pore domain potassium channel TREK-1 through direct interaction between G(βγ) and N terminus of TREK-1. The slow mode is Ca(2+) dependent and requires G(αq) activation and opening of glutamate-permeable, Ca(2+)-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.

Original languageEnglish
Pages (from-to)25-40
Number of pages16
JournalCell
Volume151
Issue number1
Publication statusPublished - 2012 Sep 28

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Woo, D. H., Han, K. S., Shim, J. W., Yoon, B. E., Kim, E., Bae, J. Y., Oh, S. J., Hwang, E. M., Marmorstein, A. D., Bae, Y. C., Park, J. Y., & Lee, C. J. (2012). TREK-1 and Best1 channels mediate fast and slow glutamate release in astrocytes upon GPCR activation. Cell, 151(1), 25-40.