ArticleACS chemical biology2014
Chemical modulation of mutant mGlu1 receptors derived from deleterious GRM1 mutations found in schizophrenics.
Article in ACS chemical biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 54 citations in OpenAlex.
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- Glycine Release Is Upregulated by Metabotropic Glutamate Receptor 1 in Mouse Hippocampus.Biomedicines · 2025Article
- Identification of a Novel GRM1 Frameshift Variant in Two Pakistani Families Broadens the Genetic Landscape of Ultra-Rare Spinocerebellar Ataxia Type 13.Cerebellum (London, England) · 2025Article
- Transcriptomic and Proteomic Changes in the Brain Along with Increasing Phenotypic Severity in a Rat Model of Neonatal Hyperbilirubinemia.International journal of molecular sciences · 2025Article
- Further Optimization of the mGluACS chemical neuroscience · 2025Article
- Discovery of VU6024578/BI02982816: An mGluJournal of medicinal chemistry · 2024Article
- Current Findings and Potential Mechanisms of KarXT (Xanomeline-Trospium) in Schizophrenia Treatment.Clinical drug investigation · 2024Review
- Cross-diagnostic determinants of cognitive functioning: the muscarinic cholinergic receptor as a model system.Translational psychiatry · 2023Review
- Genetic Variant inInternational journal of molecular sciences · 2023Article
- Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease.Pharmacological reviews · 2022Review
- Metabotropic Glutamate Receptors As Emerging Targets for the Treatment of Schizophrenia.Molecular pharmacology · 2022Review
- mGluCell reports · 2021Article
- The G Protein-Coupled Glutamate Receptors as Novel Molecular Targets in Schizophrenia Treatment-A Narrative Review.Journal of clinical medicine · 2021Review
- Activation of the mGluMolecular psychiatry · 2020Article
- Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development.European journal of nuclear medicine and molecular imaging · 2020Review
- Evaluation of Synthetic Cytochrome PACS omega · 2019Article
- Neuropharmacological Insight from Allosteric Modulation of mGlu Receptors.Trends in pharmacological sciences · 2019Review
- Targeting mGlu Receptors for Optimization of Antipsychotic Activity and Disease-Modifying Effect in Schizophrenia.Frontiers in psychiatry · 2019Review
- Activated CaMKIIMolecular pharmacology · 2018Article
- The therapeutic potential of metabotropic glutamate receptor modulation for schizophrenia.Current opinion in pharmacology · 2018Review
Corrections and comments
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
Schizophrenia is a complex and highly heterogeneous psychiatric disorder whose precise etiology remains elusive. While genome-wide association studies (GWAS) have identified risk genes, they have failed to determine if rare coding single nucleotide polymorphisms (nsSNPs) contribute in schizophrenia. Recently, two independent studies identified 12 rare, deleterious nsSNPS in the GRM1 gene, which encodes the metabotropic glutamate receptor subtype 1 (mGlu1), in schizophrenic patients. Here, we generated stable cell lines expressing the mGlu1 mutant receptors and assessed their pharmacology. Using both the endogenous agonist glutamate and the synthetic agonist DHPG, we found that several of the mutant mGlu1 receptors displayed a loss of function that was not due to a loss in plasma membrane expression. Due to a lack of mGlu1 positive allosteric modulators (PAM) tool compounds active at human mGlu1, we optimized a known mGlu4 PAM/mGlu1 NAM chemotype into a series of potent and selective mGlu1 PAMs by virtue of a double "molecular switch". Employing mGlu1 PAMs from multiple chemotypes, we demonstrate that the mutant receptors can be potentiated by small molecules and in some cases efficacy restored to that comparable to wild type mGlu1 receptors, suggesting deficits in patients with schizophrenia due to these mutations may be amenable to intervention with an mGlu1 PAM. However, in wild type animals, mGlu1 negative allosteric modulators (NAMs) are efficacious in classic models predictive of antipsychotic activity, whereas we show that mGlu1 PAMs have no effect to slight potentiation in these models. These data further highlight the heterogeneity of schizophrenia and the critical role of patient selection strategies in psychiatric clinical trials to match genotype with therapeutic mechanism.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.