Conformational pathway provides unique sensitivity to a synaptic mGluR. Academic Article uri icon

Overview

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.

publication date

  • December 5, 2019

Research

keywords

  • Protein Conformation
  • Protein Multimerization
  • Receptors, Metabotropic Glutamate

Identity

PubMed Central ID

  • PMC6895203

Scopus Document Identifier

  • 85075970140

Digital Object Identifier (DOI)

  • 10.1016/j.chemphys.2004.05.017

PubMed ID

  • 31804469

Additional Document Info

volume

  • 10

issue

  • 1