Symmetric signal transduction and negative allosteric modulation of heterodimeric mGlu1/5 receptors

Werthmann, Ruth C.; Tzouros, Manuel; Lamerz, Jens; Augustin, Angélique; Fritzius, Thorsten; Trovò, Luca; Stawarski, Michał; Raveh, Adi; Diener, Catherine; Fischer, Christophe; Gassmann, Martin; Lindemann, Lothar; Bettler, Bernhard

doi:10.1016/j.neuropharm.2020.108426

Cited by 18 publications

(17 citation statements)

References 54 publications

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“…This maneuver, mediated by interactions established between the CR domain and EC loop 2 (ECL2) of the TM domain, was speculated to be vital, as it aids in the translation and rotation of the TM domains that enabled the formation of specific inter-subunit interactions that could ameliorate the activity of mGluR [28,29,48,49]. Observations revealed through the three-dimensional structure of mGlu5 were also congruent with earlier experimental studies, all of which emphasized the importance of both intra-and inter-subunit in modulating allosteric communication between the VFT and the TM domains [25,29,[49][50][51].…”

Section: Elucidation Of Allosteric Modulation Via Full-length Structures Of Class C Gpcr Dimerssupporting

confidence: 67%

“…The formation of the heterodimeric complex between Group I mGluRs, namely mGlu1 and mGlu5, at the hippocampal neurons has been verified by Pandya et al through a series of immunoprecipitation experiments [62]. The tendency of this dimer to exist as a functional heterodimer and contribute to signal transduction was subsequently verified by Werthmann et al through functional complementation experiments in HEK293 cells [51]. Additionally, the mGlu1/5 dimer was also proposed to afford a distinct allosteric modulation pathway in comparison to their homodimeric counterparts.…”

Section: Altered Gpcr Activities Induced Through Heterodimerizationmentioning

confidence: 87%

“…Even though the homodimerization of mGluR has been widely acknowledged to regulate neuronal function, the existence of mGluR heterodimers is still as debatable as the concept of dimerization for other GPCR families. Even so, the presence of several mGluR heterodimers has been alluded through experimental studies [51,62]. The formation of the heterodimeric complex between Group I mGluRs, namely mGlu1 and mGlu5, at the hippocampal neurons has been verified by Pandya et al through a series of immunoprecipitation experiments [62].…”

Section: Altered Gpcr Activities Induced Through Heterodimerizationmentioning

confidence: 98%

“…Positive cooperativity between TM domains was also observed in mGlu2/4 and mGlu1/5 dimers. In this case, the inactive state of one protomer initiated the activation of the other through positive allosteric effects [51,63,65].…”

Section: Altered Gpcr Activities Induced Through Heterodimerizationmentioning

confidence: 99%

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Structural Characterization of Receptor–Receptor Interactions in the Allosteric Modulation of G Protein-Coupled Receptor (GPCR) Dimers

Lazim¹,

Suh²,

Lee³

et al. 2021

IJMS

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G protein-coupled receptor (GPCR) oligomerization, while contentious, continues to attract the attention of researchers. Numerous experimental investigations have validated the presence of GPCR dimers, and the relevance of dimerization in the effectuation of physiological functions intensifies the attractiveness of this concept as a potential therapeutic target. GPCRs, as a single entity, have been the main source of scrutiny for drug design objectives for multiple diseases such as cancer, inflammation, cardiac, and respiratory diseases. The existence of dimers broadens the research scope of GPCR functions, revealing new signaling pathways that can be targeted for disease pathogenesis that have not previously been reported when GPCRs were only viewed in their monomeric form. This review will highlight several aspects of GPCR dimerization, which include a summary of the structural elucidation of the allosteric modulation of class C GPCR activation offered through recent solutions to the three-dimensional, full-length structures of metabotropic glutamate receptor and γ-aminobutyric acid B receptor as well as the role of dimerization in the modification of GPCR function and allostery. With the growing influence of computational methods in the study of GPCRs, we will also be reviewing recent computational tools that have been utilized to map protein–protein interactions (PPI).

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Section: Elucidation Of Allosteric Modulation Via Full-length Structures Of Class C Gpcr Dimerssupporting

confidence: 67%

Section: Altered Gpcr Activities Induced Through Heterodimerizationmentioning

confidence: 87%

Section: Altered Gpcr Activities Induced Through Heterodimerizationmentioning

confidence: 98%

Section: Altered Gpcr Activities Induced Through Heterodimerizationmentioning

confidence: 99%

See 2 more Smart Citations

Structural Characterization of Receptor–Receptor Interactions in the Allosteric Modulation of G Protein-Coupled Receptor (GPCR) Dimers

Lazim¹,

Suh²,

Lee³

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…individual mGlu protomers are even covalently linked by a conserved cysteine residue within the disordered loop atop the LBDs [233][234][235]253 . In contrast to the closely related GABAB receptor which may form a "dimer of dimers", mGlu receptors do not seem to form higher order oligomers 222,[254][255][256] .…”

Section: Dimerization and The Lb1 Interfacementioning

confidence: 99%

Regulation and functional consequences of mGlu₄ RNA editing

Hofmann

Carrington

Keller

et al. 2021

RNA

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Metabotropic glutamate receptor 4 (mGlu4) is one of eight mGlu receptors within the Class C G protein-coupled receptor superfamily. mGlu4 is primarily localized to the presynaptic membrane of neurons where it functions as an auto and heteroreceptor controlling synaptic release of neurotransmitter. mGlu4 is implicated in numerous disorders and is a promising drug target; however, more remains to be understood about its regulation and pharmacology. Using high-throughput sequencing, we have validated and quantified an adenosine-to-inosine (A-to-I) RNA editing event that converts glutamine 124 to arginine in mGlu4; additionally, we have identified a rare but novel K129R site. Using an in vitro editing assay, we then validated the pre-mRNA duplex that allows for editing by ADAR enzymes and predicted its conservation across the mammalian species. Structural modeling of the mGlu4 protein predicts the Q124R substitution to occur in the B helix of the receptor that is critical for receptor dimerization and activation. Interestingly, editing of a receptor homodimer does not disrupt G protein activation in response to the endogenous agonist, glutamate. Using an assay designed to specifically measure heterodimer populations at the surface, however, we found that Q124R substitution decreased the propensity of mGlu4 to heterodimerize with mGlu2 and mGlu7. Our study is the first to extensively describe the extent and regulatory factors of RNA editing of mGlu4 mRNA transcripts. In addition, we have proposed a novel functional consequence of this editing event that provides insights regarding its effects in vivo and expands the regulatory capacity for mGlu receptors.

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Amyloid-β1-42 oligomers enhance mGlu5R-dependent synaptic weakening via NMDAR activation and complement C5aR1 signaling

Ng,

Salter,

Georgiou

et al. 2023

iScience

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Symmetric signal transduction and negative allosteric modulation of heterodimeric mGlu1/5 receptors

Cited by 18 publications

References 54 publications

Structural Characterization of Receptor–Receptor Interactions in the Allosteric Modulation of G Protein-Coupled Receptor (GPCR) Dimers

Structural Characterization of Receptor–Receptor Interactions in the Allosteric Modulation of G Protein-Coupled Receptor (GPCR) Dimers

Regulation and functional consequences of mGlu₄ RNA editing

Amyloid-β1-42 oligomers enhance mGlu5R-dependent synaptic weakening via NMDAR activation and complement C5aR1 signaling

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Symmetric signal transduction and negative allosteric modulation of heterodimeric mGlu1/5 receptors

Cited by 18 publications

References 54 publications

Structural Characterization of Receptor–Receptor Interactions in the Allosteric Modulation of G Protein-Coupled Receptor (GPCR) Dimers

Structural Characterization of Receptor–Receptor Interactions in the Allosteric Modulation of G Protein-Coupled Receptor (GPCR) Dimers

Regulation and functional consequences of mGlu4 RNA editing

Amyloid-β1-42 oligomers enhance mGlu5R-dependent synaptic weakening via NMDAR activation and complement C5aR1 signaling

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Product

Resources

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Regulation and functional consequences of mGlu₄ RNA editing