Conformational pathway provides unique sensitivity to a synaptic mGluR

Habrian, Chris H.; Levitz, Joshua; Vyklicky, Vojtech; Fu, Zhu; Hoagland, Adam; McCort-Tranchepain, Isabelle; Acher, Francine; Isacoff, Ehud Y.

doi:10.1038/s41467-019-13407-8

Title: Conformational pathway provides unique sensitivity to a synaptic mGluR

Journal Article · 04 December 2019 · Nature Communications

DOI: https://doi.org/10.1038/s41467-019-13407-8 · OSTI ID:1591846

Habrian, Chris H. ^[1]; Levitz, Joshua ^[2];

^[1]; Fu, Zhu ^[1]; Hoagland, Adam ^[1]; McCort-Tranchepain, Isabelle ^[3];

^[3]; Isacoff, Ehud Y. ^[4]

Univ. of California, Berkeley, CA (United States)
Univ. of California, Berkeley, CA (United States); Weill Cornell Medical College, New York, NY (United States)
Paris Descartes Univ. (France)
Univ. of California, Berkeley, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1591846

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 10; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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The intra-molecular activation mechanisms of the dimeric metabotropic glutamate receptor 1 differ depending on the type of G proteins Tateyama, Michihiro; Kubo, Yoshihiro Neuropharmacology, Vol. 61, Issue 4 https://doi.org/10.1016/j.neuropharm.2011.05.031	journal	September 2011
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Increased Potency and Selectivity for Group III Metabotropic Glutamate Receptor Agonists Binding at Dual sites Selvam, Chelliah; Lemasson, Isabelle A.; Brabet, Isabelle Journal of Medicinal Chemistry, Vol. 61, Issue 5 https://doi.org/10.1021/acs.jmedchem.7b01438	journal	January 2018
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Closed state of both binding domains of homodimeric mGlu receptors is required for full activity Kniazeff, Julie; Bessis, Anne-Sophie; Maurel, Damien Nature Structural & Molecular Biology, Vol. 11, Issue 8 https://doi.org/10.1038/nsmb794	journal	July 2004
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Optical measurement of synaptic glutamate spillover and reuptake by linker optimized glutamate-sensitive fluorescent reporters Hires, S. A.; Zhu, Y.; Tsien, R. Y. Proceedings of the National Academy of Sciences, Vol. 105, Issue 11 https://doi.org/10.1073/pnas.0712008105	journal	March 2008
Pathway and mechanism of drug binding to G-protein-coupled receptors Dror, Ron O.; Pan, Albert C.; Arlow, Daniel H. Proceedings of the National Academy of Sciences, Vol. 108, Issue 32 https://doi.org/10.1073/pnas.1104614108	journal	July 2011
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Dual optical control and mechanistic insights into photoswitchable group II and III metabotropic glutamate receptors Levitz, Joshua; Broichhagen, Johannes; Leippe, Philipp Proceedings of the National Academy of Sciences, Vol. 114, Issue 17 https://doi.org/10.1073/pnas.1619652114	journal	April 2017
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