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Title: Conformational pathway provides unique sensitivity to a synaptic mGluR

Abstract

Metabotropic glutamate receptors (mGluRs) are dimeric G-protein-coupled receptors that operate at synapses. Macroscopic and single molecule FRET to monitor structural rearrangements in the ligand binding domain (LBD) of the mGluR7/7 homodimer revealed it to have an apparent affinity ~4000-fold lower than other mGluRs and a maximal activation of only ~10%, seemingly too low for activation at synapses. However, mGluR7 heterodimerizes, and we find it to associate with mGluR2 in the hippocampus. Strikingly, the mGluR2/7 heterodimer has high affinity and efficacy. mGluR2/7 shows cooperativity in which an unliganded subunit greatly enhances activation by agonist bound to its heteromeric partner, and a unique conformational pathway to activation, in which mGluR2/7 partially activates in the Apo state, even when its LBDs are held open by antagonist. High sensitivity and an unusually broad dynamic range should enable mGluR2/7 to respond to both glutamate transients from nearby release and spillover from distant synapses.

Authors:
 [1];  [2]; ORCiD logo [1];  [1];  [1];  [3]; ORCiD logo [3];  [4]
  1. Univ. of California, Berkeley, CA (United States)
  2. Univ. of California, Berkeley, CA (United States); Weill Cornell Medical College, New York, NY (United States)
  3. Paris Descartes Univ. (France)
  4. Univ. of California, Berkeley, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1591846
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 10; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; biophysics; neuroscience

Citation Formats

Habrian, Chris H., Levitz, Joshua, Vyklicky, Vojtech, Fu, Zhu, Hoagland, Adam, McCort-Tranchepain, Isabelle, Acher, Francine, and Isacoff, Ehud Y. Conformational pathway provides unique sensitivity to a synaptic mGluR. United States: N. p., 2019. Web. doi:10.1038/s41467-019-13407-8.
Habrian, Chris H., Levitz, Joshua, Vyklicky, Vojtech, Fu, Zhu, Hoagland, Adam, McCort-Tranchepain, Isabelle, Acher, Francine, & Isacoff, Ehud Y. Conformational pathway provides unique sensitivity to a synaptic mGluR. United States. doi:10.1038/s41467-019-13407-8.
Habrian, Chris H., Levitz, Joshua, Vyklicky, Vojtech, Fu, Zhu, Hoagland, Adam, McCort-Tranchepain, Isabelle, Acher, Francine, and Isacoff, Ehud Y. Thu . "Conformational pathway provides unique sensitivity to a synaptic mGluR". United States. doi:10.1038/s41467-019-13407-8. https://www.osti.gov/servlets/purl/1591846.
@article{osti_1591846,
title = {Conformational pathway provides unique sensitivity to a synaptic mGluR},
author = {Habrian, Chris H. and Levitz, Joshua and Vyklicky, Vojtech and Fu, Zhu and Hoagland, Adam and McCort-Tranchepain, Isabelle and Acher, Francine and Isacoff, Ehud Y.},
abstractNote = {Metabotropic glutamate receptors (mGluRs) are dimeric G-protein-coupled receptors that operate at synapses. Macroscopic and single molecule FRET to monitor structural rearrangements in the ligand binding domain (LBD) of the mGluR7/7 homodimer revealed it to have an apparent affinity ~4000-fold lower than other mGluRs and a maximal activation of only ~10%, seemingly too low for activation at synapses. However, mGluR7 heterodimerizes, and we find it to associate with mGluR2 in the hippocampus. Strikingly, the mGluR2/7 heterodimer has high affinity and efficacy. mGluR2/7 shows cooperativity in which an unliganded subunit greatly enhances activation by agonist bound to its heteromeric partner, and a unique conformational pathway to activation, in which mGluR2/7 partially activates in the Apo state, even when its LBDs are held open by antagonist. High sensitivity and an unusually broad dynamic range should enable mGluR2/7 to respond to both glutamate transients from nearby release and spillover from distant synapses.},
doi = {10.1038/s41467-019-13407-8},
journal = {Nature Communications},
number = 1,
volume = 10,
place = {United States},
year = {2019},
month = {12}
}

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