scholarly journals Conformational pathway provides unique sensitivity to a synaptic mGluR

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Chris H. Habrian ◽  
Joshua Levitz ◽  
Vojtech Vyklicky ◽  
Zhu Fu ◽  
Adam Hoagland ◽  
...  
Keyword(s):  
Single Molecule ◽  
Metabotropic Glutamate Receptors ◽  
Dynamic Range ◽  
High Sensitivity ◽  
G Protein Coupled Receptors ◽  
Metabotropic Glutamate ◽  
Single Molecule Fret ◽  
Broad Dynamic Range ◽  
Maximal Activation ◽  
G Protein Coupled

AbstractMetabotropic 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.

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

2021 ◽  
Author(s):  
Jordana K. Thibado ◽  
Jean-Yves Tano ◽  
Joon Lee ◽  
Leslie Salas-Estrada ◽  
Davide Provasi ◽  
...  
Keyword(s):  
Glutamate Receptors ◽  
Single Molecule ◽  
Metabotropic Glutamate Receptors ◽  
Transmembrane Domain ◽  
Critical Role ◽  
Transmembrane Helix ◽  
Variable Region ◽  
Metabotropic Glutamate ◽  
Initial Activation ◽  
G Protein Coupled

AbstractThe 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 informs a working model of inter-TMD rearrangement that drives mGluR function.

scholarly journals Structural Dynamics of the Full-Length Metabotropic Glutamate Receptors by Single-Molecule FRET

2016 ◽  
Vol 110 (3) ◽  
pp. 637a
Author(s):  
Anne-Marinette Cao ◽  
Fataneh Fatemi ◽  
Philippe Rondard ◽  
Jean-Philippe Pin ◽  
Emmanuel Margeat
Keyword(s):  
Glutamate Receptors ◽  
Structural Dynamics ◽  
Single Molecule ◽  
Metabotropic Glutamate Receptors ◽  
Full Length ◽  
Metabotropic Glutamate ◽  
Single Molecule Fret

scholarly journals Allosteric modulators enhance agonist efficacy by increasing the residence time of a GPCR in the active state

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Anne-Marinette Cao ◽  
Robert B. Quast ◽  
Fataneh Fatemi ◽  
Philippe Rondard ◽  
Jean-Philippe Pin ◽  
...  
Keyword(s):  
Single Molecule ◽  
Metabotropic Glutamate Receptors ◽  
Transmembrane Domain ◽  
Active State ◽  
Brain Diseases ◽  
Allosteric Modulators ◽  
Metabotropic Glutamate ◽  
Single Molecule Fret ◽  
Agonist Action ◽  
Subtype Selectivity

AbstractMuch hope in drug development comes from the discovery of positive allosteric modulators (PAM) that display target subtype selectivity and act by increasing agonist potency and efficacy. How such compounds can allosterically influence agonist action remains unclear. Metabotropic glutamate receptors (mGlu) are G protein-coupled receptors that represent promising targets for brain diseases, and for which PAMs acting in the transmembrane domain have been developed. Here, we explore the effect of a PAM on the structural dynamics of mGlu2 in optimized detergent micelles using single molecule FRET at submillisecond timescales. We show that glutamate only partially stabilizes the extracellular domains in the active state. Full activation is only observed in the presence of a PAM or the Gi protein. Our results provide important insights on the role of allosteric modulators in mGlu activation, by stabilizing the active state of a receptor that is otherwise rapidly oscillating between active and inactive states.

scholarly journals Sub-millisecond conformational dynamics of the A2A adenosine receptor revealed by single-molecule FRET

2020 ◽  
Author(s):  
Ivan Maslov ◽  
Oleksandr Volkov ◽  
Polina Khorn ◽  
Philipp Orekhov ◽  
Anastasiia Gusach ◽  
...  
Keyword(s):  
Single Molecule ◽  
Adenosine Receptor ◽  
Conformational Dynamics ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
G Protein Coupled Receptors ◽  
A2a Adenosine Receptor ◽  
Single Molecule Fret ◽  
Lipid Nanodiscs ◽  
G Protein Coupled

AbstractThe complex pharmacology of G-protein-coupled receptors (GPCRs) is defined by their multi-state conformational dynamics. Single-molecule Förster Resonance Energy Transfer (smFRET) is well-suited to quantify dynamics for individual protein molecules, however, its application to GPCRs is challenging; therefore, smFRET has been limited to studies of interreceptor interactions in cellular membranes and receptors in detergent environments. Here, we performed smFRET experiments on functionally active human A2A adenosine receptor (A2AAR) molecules embedded in freely diffusing lipid nanodiscs to study their intramolecular conformational dynamics. We propose a dynamic model of A2AAR activation that involves a slow (>2 ms) exchange between the active-like and inactive-like conformations in both apo and antagonist-bound A2AAR, explaining the receptor’s constitutive activity. For the agonist-bound A2AAR, we detected faster (390±80 μs) ligand efficacy-dependent dynamics. This work establishes a general smFRET platform for GPCR investigations that can potentially be used for drug screening and/or mechanism-of-action studies.

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

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Jordana K Thibado ◽  
Jean-Yves Tano ◽  
Joon Lee ◽  
Leslie Salas-Estrada ◽  
Davide Provasi ◽  
...  
Keyword(s):  
Glutamate Receptors ◽  
Single Molecule ◽  
Metabotropic Glutamate Receptors ◽  
Transmembrane Domain ◽  
Critical Role ◽  
Transmembrane Helix ◽  
Variable Region ◽  
Metabotropic Glutamate ◽  
Initial Activation ◽  
G Protein Coupled

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.

scholarly journals The G Protein-Coupled Glutamate Receptors as Novel Molecular Targets in Schizophrenia Treatment—A Narrative Review

2021 ◽  
Vol 10 (7) ◽  
pp. 1475
Author(s):  
Waldemar Kryszkowski ◽  
Tomasz Boczek
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Glutamate Release ◽  
Molecular Targets ◽  
Brain Regions ◽  
Psychotic Symptoms ◽  
Unknown Etiology ◽  
Metabotropic Glutamate ◽  
G Protein Coupled

Schizophrenia is a severe neuropsychiatric disease with an unknown etiology. The research into the neurobiology of this disease led to several models aimed at explaining the link between perturbations in brain function and the manifestation of psychotic symptoms. The glutamatergic hypothesis postulates that disrupted glutamate neurotransmission may mediate cognitive and psychosocial impairments by affecting the connections between the cortex and the thalamus. In this regard, the greatest attention has been given to ionotropic NMDA receptor hypofunction. However, converging data indicates metabotropic glutamate receptors as crucial for cognitive and psychomotor function. The distribution of these receptors in the brain regions related to schizophrenia and their regulatory role in glutamate release make them promising molecular targets for novel antipsychotics. This article reviews the progress in the research on the role of metabotropic glutamate receptors in schizophrenia etiopathology.

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