Mechanisms of differential desensitization of metabotropic glutamate receptors

Abreu, Nohely; Acosta-Ruiz, Amanda; Xiang, Guoqing; Levitz, Joshua

doi:10.1016/j.celrep.2021.109050

Cited by 29 publications

(50 citation statements)

References 102 publications

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“…Indeed, D2R, which natively terminates after H8, can measurably recruit barr2 in the GRK KO cells in the absence of GRK phosphorylation. A recent report also suggest an inhibitory role of the metabotropic glutamate 2 receptor C tail in barr2 recruitment (Abreu et al, 2021). Notably, the C-terminal region beyond H8 is unresolved in nearly all reported GPCR structural models.…”

Section: Discussionmentioning

confidence: 99%

GPCR-mediated β-arrestin activation deconvoluted with single-molecule precision

Asher

Terry

Gregorio

et al. 2022

Cell

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Section: Discussionmentioning

confidence: 99%

GPCR-mediated β-arrestin activation deconvoluted with single-molecule precision

Asher

Terry

Gregorio

et al. 2022

Cell

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“…A single injection of 30 mg/kg BRD0705 normalizes audiogenic seizure susceptibility in Fmr1-KO mice but has no effect on seizure incidence in Fmr1-KO mice treated with chronic (3 doses over 5 days) 2.0 mg/kg CTEP (two-tailed Fisher's exact test: Fmr1-KO 4x vehicle vs. Fmr1-KO 3x vehicle + BRD0705 p = 0.0036; two-tailed Fisher's exact test: Fmr1-KO 4x vehicle vs. Fmr1-KO 3x CTEP + BRD0705 p = 0.2357). coupling of the receptors to their G-proteins (51)(52)(53). It is possible that an inverse process-sensitization or increased expression of mGluR5-after chronic NAM treatment accounts for the diminished effectiveness of treatment, but several lines of evidence suggest otherwise.…”

Section: Discussionmentioning

confidence: 99%

mGluR5 Negative Modulators for Fragile X: Treatment Resistance and Persistence

et al. 2021

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Fragile X syndrome (FXS) is caused by silencing of the human FMR1 gene and is the leading monogenic cause of intellectual disability and autism. Abundant preclinical data indicated that negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5) might be efficacious in treating FXS in humans. Initial attempts to translate these findings in clinical trials have failed, but these failures provide the opportunity for new discoveries that will improve future trials. The emergence of acquired treatment resistance (“tolerance”) after chronic administration of mGluR5 NAMs is a potential factor in the lack of success. Here we confirm that FXS model mice display acquired treatment resistance after chronic treatment with the mGluR5 NAM CTEP in three assays commonly examined in the mouse model of FXS: (1) audiogenic seizure susceptibility, (2) sensory cortex hyperexcitability, and (3) hippocampal protein synthesis. Cross-tolerance experiments suggest that the mechanism of treatment resistance likely occurs at signaling nodes downstream of glycogen synthase kinase 3α (GSK3α), but upstream of protein synthesis. The rapid emergence of tolerance to CTEP begs the question of how previous studies showed an improvement in inhibitory avoidance (IA) cognitive performance after chronic treatment. We show here that this observation was likely explained by timely inhibition of mGluR5 during a critical period, as brief CTEP treatment in juvenile mice is sufficient to provide a persistent improvement of IA behavior measured many weeks later. These data will be important to consider when designing future fragile X clinical trials using compounds that target the mGluR5-to-protein synthesis signaling cascade.

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“…A transcript of the MC1R (MC1R-203) naturally promotes such biased signaling toward the MAPK pathway [280]. Mutants of metabolic glutamate receptors (mGluR3 G848E ) can promote such biased signaling, characterized by prolonged internalization of the receptor [281]. This mutation is found in rare cases of cutaneous melanoma (<1%) [110].…”

Section: β-Arrestin Signalingmentioning

confidence: 99%

Targeting GPCRs and Their Signaling as a Therapeutic Option in Melanoma

Raymond

Aktary

Larue

et al. 2022

Cancers

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G-protein-coupled receptors (GPCRs) serve prominent roles in melanocyte lineage physiology, with an impact at all stages of development, as well as on mature melanocyte functions. GPCR ligands are present in the skin and regulate melanocyte homeostasis, including pigmentation. The role of GPCRs in the regulation of pigmentation and, consequently, protection against external aggression, such as ultraviolet radiation, has long been established. However, evidence of new functions of GPCRs directly in melanomagenesis has been highlighted in recent years. GPCRs are coupled, through their intracellular domains, to heterotrimeric G-proteins, which induce cellular signaling through various pathways. Such signaling modulates numerous essential cellular processes that occur during melanomagenesis, including proliferation and migration. GPCR-associated signaling in melanoma can be activated by the binding of paracrine factors to their receptors or directly by activating mutations. In this review, we present melanoma-associated alterations of GPCRs and their downstream signaling and discuss the various preclinical models used to evaluate new therapeutic approaches against GPCR activity in melanoma. Recent striking advances in our understanding of the structure, function, and regulation of GPCRs will undoubtedly broaden melanoma treatment options in the future.

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Mechanisms of differential desensitization of metabotropic glutamate receptors

Cited by 29 publications

References 102 publications

GPCR-mediated β-arrestin activation deconvoluted with single-molecule precision

GPCR-mediated β-arrestin activation deconvoluted with single-molecule precision

mGluR5 Negative Modulators for Fragile X: Treatment Resistance and Persistence

Targeting GPCRs and Their Signaling as a Therapeutic Option in Melanoma

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