Differences in interactions between transmembrane domains tune the activation of metabotropic glutamate receptors

  1. Jordana K Thibado
  2. Jean-Yves Tano
  3. Joon Lee
  4. Leslie Salas-Estrada
  5. Davide Provasi
  6. Alexa Strauss
  7. Joao Marcelo Lamim Ribeiro
  8. Guoqing Xiang
  9. Johannes Broichhagen
  10. Marta Filizola
  11. Martin J Lohse
  12. Joshua Levitz  Is a corresponding author
  1. Weill Cornell Graduate School of Medical Sciences, United States
  2. Max Delbrück Center for Molecular Medicine, Germany
  3. Weill Cornell Medicine, United States
  4. Icahn School of Medicine at Mount Sinai, United States
  5. Forschungsinstitut für Molekulare Pharmakologie, Germany

Abstract

The metabotropic glutamate receptors (mGluRs) form a family of neuromodulatory G protein-coupled receptors that contain both a seven-helix transmembrane domain (TMD) and a large extracellular ligand-binding domain (LBD) which enables stable dimerization. While numerous studies have revealed variability across subtypes in the initial activation steps at the level of LBD dimers, an understanding of inter-TMD interaction and rearrangement remains limited. Here we use a combination of single molecule fluorescence, molecular dynamics, functional assays, and conformational sensors to reveal that distinct TMD assembly properties drive differences between mGluR subtypes. We uncover a variable region within transmembrane helix 4 (TM4) that contributes to homo- and heterodimerization in a subtype-specific manner and tunes orthosteric, allosteric and basal activation. We also confirm a critical role for a conserved inter-TM6 interface in stabilizing the active state during orthosteric or allosteric activation. Together this study shows that inter-TMD assembly and dynamic rearrangement drive mGluR function with distinct properties between subtypes.

Data availability

We have provided source data files for all relevant figures.

Article and author information

Author details

  1. Jordana K Thibado

    Physiology, Biophysics and Systems Biology Graduate Program, Weill Cornell Graduate School of Medical Sciences, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jean-Yves Tano

    Receptor Signaling Lab, Max Delbrück Center for Molecular Medicine, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Joon Lee

    Department of Biochemistry, Weill Cornell Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Leslie Salas-Estrada

    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Davide Provasi

    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2868-303X
  6. Alexa Strauss

    Tri-Institutional PhD Program in Chemical Biology, Weill Cornell Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Joao Marcelo Lamim Ribeiro

    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Guoqing Xiang

    Department of Biochemistry, Weill Cornell Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Johannes Broichhagen

    Department of Chemical Biology, Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3084-6595
  10. Marta Filizola

    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Martin J Lohse

    Receptor Signaling Lab, Max Delbrück Center for Molecular Medicine, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Joshua Levitz

    Department of Biochemistry, Weill Cornell Medicine, New York, United States
    For correspondence
    jtl2003@med.cornell.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8169-6323

Funding

National Institute of General Medical Sciences (R35 GM124731)

  • Joshua Levitz

National Science Foundation (GRFP)

  • Jordana K Thibado

National Institute on Drug Abuse (DA038882)

  • Marta Filizola

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2021, Thibado et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,115
    views
  • 312
    downloads
  • 22
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Jordana K Thibado
  2. Jean-Yves Tano
  3. Joon Lee
  4. Leslie Salas-Estrada
  5. Davide Provasi
  6. Alexa Strauss
  7. Joao Marcelo Lamim Ribeiro
  8. Guoqing Xiang
  9. Johannes Broichhagen
  10. Marta Filizola
  11. Martin J Lohse
  12. Joshua Levitz
(2021)
Differences in interactions between transmembrane domains tune the activation of metabotropic glutamate receptors
eLife 10:e67027.
https://doi.org/10.7554/eLife.67027

Share this article

https://doi.org/10.7554/eLife.67027

Further reading

    1. Neuroscience
    John P Grogan, Matthias Raemaekers ... Sanjay G Manohar
    Research Article

    Motivation depends on dopamine, but might be modulated by acetylcholine which influences dopamine release in the striatum, and amplifies motivation in animal studies. A corresponding effect in humans would be important clinically, since anticholinergic drugs are frequently used in Parkinson’s disease, a condition that can also disrupt motivation. Reward and dopamine make us more ready to respond, as indexed by reaction times (RT), and move faster, sometimes termed vigour. These effects may be controlled by preparatory processes that can be tracked using electroencephalography (EEG). We measured vigour in a placebo-controlled, double-blinded study of trihexyphenidyl (THP), a muscarinic antagonist, with an incentivised eye movement task and EEG. Participants responded faster and with greater vigour when incentives were high, but THP blunted these motivational effects, suggesting that muscarinic receptors facilitate invigoration by reward. Preparatory EEG build-up (contingent negative variation [CNV]) was strengthened by high incentives and by muscarinic blockade, although THP reduced the incentive effect. The amplitude of preparatory activity predicted both vigour and RT, although over distinct scalp regions; frontal activity predicted vigour, whereas a larger, earlier, central component predicted RT. The incentivisation of RT was partly mediated by the CNV, though vigour was not. Moreover, the CNV mediated the drug’s effect on dampening incentives, suggesting that muscarinic receptors underlie the motivational influence on this preparatory activity. Taken together, these findings show that a muscarinic blocker impairs motivated action in healthy people, and that medial frontal preparatory neural activity mediates this for RT.

    1. Neuroscience
    Samyogita Hardikar, Bronte Mckeown ... Jonathan Smallwood
    Research Article

    Complex macro-scale patterns of brain activity that emerge during periods of wakeful rest provide insight into the organisation of neural function, how these differentiate individuals based on their traits, and the neural basis of different types of self-generated thoughts. Although brain activity during wakeful rest is valuable for understanding important features of human cognition, its unconstrained nature makes it difficult to disentangle neural features related to personality traits from those related to the thoughts occurring at rest. Our study builds on recent perspectives from work on ongoing conscious thought that highlight the interactions between three brain networks – ventral and dorsal attention networks, as well as the default mode network. We combined measures of personality with state-of-the-art indices of ongoing thoughts at rest and brain imaging analysis and explored whether this ‘tri-partite’ view can provide a framework within which to understand the contribution of states and traits to observed patterns of neural activity at rest. To capture macro-scale relationships between different brain systems, we calculated cortical gradients to describe brain organisation in a low-dimensional space. Our analysis established that for more introverted individuals, regions of the ventral attention network were functionally more aligned to regions of the somatomotor system and the default mode network. At the same time, a pattern of detailed self-generated thought was associated with a decoupling of regions of dorsal attention from regions in the default mode network. Our study, therefore, establishes that interactions between attention systems and the default mode network are important influences on ongoing thought at rest and highlights the value of integrating contemporary perspectives on conscious experience when understanding patterns of brain activity at rest.