Activation of a Dimeric Metabotropic Glutamate Receptor by Intersubunit Rearrangement

Brock, Carsten; Oueslati, Nadia; Soler, Stephan; Boudier, Laure; Rondard, Philippe; Pin, Jean‐Philippe

doi:10.1074/jbc.m702542200

Cited by 95 publications

(102 citation statements)

References 47 publications

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“…In such functional heterodimers the two splice variants are therefore present, as the activation of VFT of the mGluR1aF/P has to be transferred on the YADAmGluR1b heptahelical domain to activate Gproteins. It was shown previously, that such trans-activation occurs in mGlu receptors (Brock et al, 2007;Goudet et al, 2005;Hlavackova et al, 2005). …”

Section: Discussionmentioning

confidence: 80%

“…Another potential mechanism would be parallel trafficking of mGluR1b homodimers with mGluR1a homodimers. However, the possibility, that the mGluR1b homodimer surface expression could be driven by mGluR1a homodimer trafficking would require formation of higher-order oligomers, that were not observed for mGlu receptors on cell surface (Brock et al, 2007). It should be stressed out that in this paper receptors on the cell surface were studied and as such this might not reflect a situation in sub cellular fractions in trafficking compartments.…”

Section: Discussionmentioning

confidence: 87%

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Surface expression of metabotropic glutamate receptor variants mGluR1a and mGluR1b in transfected HEK293 cells

et al. 2008

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Here we investigated consequences of interactions between long mGluR1a and short mGluR1b variants. Our results show, that mGluR1a interferes with mGluR1b trafficking to the cell surface in HEK293 transfected cells. Moreover, we show that swapping long mGluR1a and/or short mGluR1b C-termini with corresponding regions in chimerical GB1 and GB2 γ-amino butyric acid b (GABAb) receptor subunits does not exclude their heterodimerization.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 87%

Surface expression of metabotropic glutamate receptor variants mGluR1a and mGluR1b in transfected HEK293 cells

et al. 2008

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“…To test this hypothesis, we took advantage of the quality control system of the GABA B receptor to produce "heterodimeric" mGluR (13,30), in which only one subunit carries the C500A mutation. As previously reported, the C-terminal tail of mGlu2 was replaced either by that of the GABA B1 subunit (mGlu2-C1) carrying the natural retention signal RSRR or by a modified GABA B2 C-terminal tail carrying a retention signal KKDL at its C terminus, just after the coiled coil domain (mGlu2-C2).…”

Section: Resultsmentioning

confidence: 99%

Interdomain movements in metabotropic glutamate receptor activation

Huang

Cao

Jiang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Many cell surface receptors are multimeric proteins, composed of several structural domains, some involved in ligand recognition, whereas others are responsible for signal transduction. In most cases, the mechanism of how ligand interaction in the extracellular domains leads to the activation of effector domains remains largely unknown. Here we examined how the extracellular ligand binding to the venus flytrap (VFT) domains of the dimeric metabotropic glutamate receptors activate the seven transmembrane (7TM) domains responsible for G protein activation. These two domains are interconnected by a cysteine-rich domain (CRD). We show that any of the four disulfide bridges of the CRD are required for the allosteric coupling between the VFT and the 7TM domains. More importantly, we show that a specific association of the two CRDs corresponds to the active state of the receptor. Indeed, a specific crosslinking of the CRDs with intersubunit disulfide bridges leads to fully constitutively active receptors, no longer activated by agonists nor by allosteric modulators. These data demonstrate that intersubunit movement at the level of the CRDs represents a key step in metabotropic glutamate receptor activation.transmembrane signaling | G protein-coupled receptor | allosteric modulation M ost cell surface receptors are multimeric complexes of which each subunit is produced through the association of different domains throughout evolution (1-5). The activation of such receptor complexes is a result of coordinated conformational changes or movement of these different domains. Although an increasing amount of 3D crystal structures are becoming available, there is still limited information available on the structural basis of interdomain communication.Class C G protein-coupled receptors (GPCRs) represent key examples of such receptor complexes (6, 7). These receptors are obligatory dimers, either homo-or heterodimers, made by the association of two domains over evolutionary time; an extracellular bilobate venus flytrap (VFT) domain associated with a G protein activating 7 transmembrane (7TM) domain (Fig. 1A) (8). The VFTs are evolved from certain types of bacterial periplasmic binding proteins, especially those of the leucine-isoleucinevaline binding protein family involved in the transport of amino acids, sugars, or ions. Not surprisingly, class C GPCRs are activated by amino acids, i.e., the receptors for the two major neurotransmitters, the eight metabotropic glutamate receptors (mGluRs), and the GABA B receptor; sugar (the sweet taste receptors); or ions [the calcium-sensing receptor (CaSR)]. Accordingly, class C GPCRs represent exciting new targets for drug development for both the pharmaceutical and food industries, as illustrated by the number of drugs targeting these receptors already on the market (the GABA B receptor agonist baclofen, umami compounds, and various sweeteners such as aspartame, and cinacalcet, a positive allosteric modulator of the CaSR), and those in clinical trials (9-11).The precise mechanisms of how...

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“…1A). These receptors are strict dimers (4)(5)(6), and each subunit is made of a large ECD associated with a seven-helix TMD responsible for G-protein activation and downstream signaling (7). The mGluRs are key elements involved in the regulation of synaptic activity (8), and therefore they represent promising targets in drug development for the treatment of multiple neurologic and psychiatric diseases (9).…”

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confidence: 99%

Illuminating the activation mechanisms and allosteric properties of metabotropic glutamate receptors

Doumazane

Scholler

Fabre

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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In multimeric cell-surface receptors, the conformational changes of the extracellular ligand-binding domains (ECDs) associated with receptor activation remain largely unknown. This is the case for the dimeric metabotropic glutamate receptors even though a number of ECD structures have been solved. Here, using an innovative approach based on cell-surface labeling and FRET, we demonstrate that a reorientation of the ECDs is associated with receptor and G-protein activation. Our approach helps identify partial agonists and highlights allosteric interactions between the effector and binding domains. Any approach expected to stabilize the active conformation of the effector domain increased the agonist potency in stabilizing the active ECDs conformation. These data provide key information on the structural dynamics and drug action at metabotropic glutamate receptors and validate an approach for tackling such analysis on other receptors.M any cell-surface receptors are multimers of proteins composed of several domains (1-3), including extracellular domains (ECDs) involved in endogenous ligand recognition and transmembrane domains (TMDs) responsible for intracellular signal transduction. Analysis of the conformational changes of the ECDs associated with receptor activation is crucial to understand the detailed mechanism involved in receptor activation and for the development of new innovative drugs. However, limited information is available on how the conformational changes in these proteins lead to receptor activation, especially in living cells.The eight glutamate-activated G-protein-coupled receptors (GPCRs), called "metabotropic glutamate receptors" (mGluRs), are key examples of multidomain and multimeric receptors (Fig. 1A). These receptors are strict dimers (4-6), and each subunit is made of a large ECD associated with a seven-helix TMD responsible for G-protein activation and downstream signaling (7). The mGluRs are key elements involved in the regulation of synaptic activity (8), and therefore they represent promising targets in drug development for the treatment of multiple neurologic and psychiatric diseases (9). More generally, the mGluRs are part of the class C GPCR family that contains structurally related receptors such as the receptors for sweet and umami taste, calcium, basic amino acids, and the inhibitory neurotransmitter GABA (10, 11).Crystallographic studies of the isolated dimeric ECDs and mutagenesis analyses have provided a clear view of the structure of the dimeric ECD and of the initial steps of mGluR activation. The ECD is composed of a Venus flytrap (VFT) bilobate domain containing the agonist binding site (12-15) and a cysteine-rich domain (CRD) that connects the VFT to the TMD (16). The VFTs exist in two major states: an open state (o) in absence of ligand and stabilized by antagonists, and a closed state (c) stabilized by agonists and required for receptor activation (12-15). The VFT dimer is in equilibrium between various conformations, depending on whether one or two VFTs are open or cl...

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Activation of a Dimeric Metabotropic Glutamate Receptor by Intersubunit Rearrangement

Cited by 95 publications

References 47 publications

Surface expression of metabotropic glutamate receptor variants mGluR1a and mGluR1b in transfected HEK293 cells

Surface expression of metabotropic glutamate receptor variants mGluR1a and mGluR1b in transfected HEK293 cells

Interdomain movements in metabotropic glutamate receptor activation

Illuminating the activation mechanisms and allosteric properties of metabotropic glutamate receptors

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