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.

Details

Title
Conformational pathway provides unique sensitivity to a synaptic mGluR
Author
Habrian, Chris H 1 ; Levitz, Joshua 2 ; Vyklicky, Vojtech 3   VIAFID ORCID Logo  ; Zhu, Fu 3 ; Hoagland, Adam 3 ; McCort-Tranchepain, Isabelle 4 ; Acher, Francine 4   VIAFID ORCID Logo  ; Isacoff, Ehud Y 5 

1  Biophysics Graduate Group, University of California, Berkeley, CA, USA 
2  Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA; Department of Biochemistry, Weill Cornell Medical College, New York, NY, USA 
3  Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA 
4  Paris Descartes University, Paris, France 
5  Biophysics Graduate Group, University of California, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA; Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA; Molecular Biology & Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA 
Pages
1-13
Publication year
2019
Publication date
Dec 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-13407-8
ProQuest document ID
2322135177
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.