Conformational pathway provides unique sensitivity to a synaptic mGluR

Nat Commun. 2019 Dec 5;10(1):5572. doi: 10.1038/s41467-019-13407-8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Glutamic Acid / metabolism
  • HEK293 Cells
  • Humans
  • Mice
  • Microscopy, Fluorescence
  • Patch-Clamp Techniques
  • Protein Conformation*
  • Protein Multimerization*
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / chemistry*
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / metabolism
  • Synapses / genetics
  • Synapses / metabolism
  • Synapses / physiology


  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2
  • metabotropic glutamate receptor 7
  • Glutamic Acid