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Article Dans Une Revue Nature Communications Année : 2019

Conformational pathway provides unique sensitivity to a synaptic mGluR

Résumé

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 onlỹ 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 hetero-dimer 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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Dates et versions

hal-02401013 , version 1 (09-12-2019)

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Chris H Habrian, Joshua Levitz, Vojtech Vyklicky, Zhu Fu, Adam Hoagland, et al.. Conformational pathway provides unique sensitivity to a synaptic mGluR. Nature Communications, 2019, ⟨10.1038/s41467-019-13407-8⟩. ⟨hal-02401013⟩
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