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Conformational pathway provides unique sensitivity to a synaptic mGluR

Author

Listed:
  • Chris H. Habrian

    (University of California)

  • Joshua Levitz

    (University of California
    Weill Cornell Medical College)

  • Vojtech Vyklicky

    (University of California)

  • Zhu Fu

    (University of California)

  • Adam Hoagland

    (University of California)

  • Isabelle McCort-Tranchepain

    (Paris Descartes University)

  • Francine Acher

    (Paris Descartes University)

  • Ehud Y. Isacoff

    (University of California
    University of California
    University of California
    Lawrence Berkeley National Laboratory)

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.

Suggested Citation

  • Chris H. Habrian & Joshua Levitz & Vojtech Vyklicky & Zhu Fu & Adam Hoagland & Isabelle McCort-Tranchepain & Francine Acher & Ehud Y. Isacoff, 2019. "Conformational pathway provides unique sensitivity to a synaptic mGluR," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13407-8
    DOI: 10.1038/s41467-019-13407-8
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    Cited by:

    1. Kento Ojima & Wataru Kakegawa & Tokiwa Yamasaki & Yuta Miura & Masayuki Itoh & Yukiko Michibata & Ryou Kubota & Tomohiro Doura & Eriko Miura & Hiroshi Nonaka & Seiya Mizuno & Satoru Takahashi & Michis, 2022. "Coordination chemogenetics for activation of GPCR-type glutamate receptors in brain tissue," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Alexa Strauss & Alberto J. Gonzalez-Hernandez & Joon Lee & Nohely Abreu & Purushotham Selvakumar & Leslie Salas-Estrada & Melanie Kristt & Anisul Arefin & Kevin Huynh & Dagan C. Marx & Kristen Gillila, 2024. "Structural basis of positive allosteric modulation of metabotropic glutamate receptor activation and internalization," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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