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Metabotropic glutamate receptor 3 as a potential therapeutic target for psychiatric and neurological disorders.

ABSTRACT: Glutamate is a major excitatory neurotransmitter in the central nervous system (CNS) and abnormalities in the glutamatergic system underlie various CNS disorders. As metabotropic glutamate receptor 3 (mGlu₃ receptor) regulates glutamatergic transmission in various brain areas, emerging literature suggests that targeting mGlu₃ receptors can be a novel approach to the treatment of psychiatric and neurological disorders. For example, mGlu₃ receptor negative allosteric modulators (NAMs) induce rapid antidepressant-like effects in both acute and chronic stress models. Activation of mGlu₃ receptors can enhance cognition in the rodents modeling schizophrenia-like pathophysiology. The mGlu₃ receptors expressed in the astrocytes induce neuroprotective effects. Although polymorphisms in GRM3 have been shown to be associated with addiction, there is not significant evidence about the efficacy of mGlu₃ receptor ligands in rodent models of addiction. Collectively, drugs targeting mGlu₃ receptors may provide an alternative approach to fill the unmet clinical need for safer and more efficacious therapeutics for CNS disorders.

SUBMITTER: Dogra S

PROVIDER: S-EPMC9729465 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Metabotropic glutamate receptor 3 as a potential therapeutic target for psychiatric and neurological disorders.

Dogra Shalini S Putnam Jason J Conn P Jeffrey PJ

Pharmacology, biochemistry, and behavior 20221117

Glutamate is a major excitatory neurotransmitter in the central nervous system (CNS) and abnormalities in the glutamatergic system underlie various CNS disorders. As metabotropic glutamate receptor 3 (mGlu<sub>3</sub> receptor) regulates glutamatergic transmission in various brain areas, emerging literature suggests that targeting mGlu<sub>3</sub> receptors can be a novel approach to the treatment of psychiatric and neurological disorders. For example, mGlu<sub>3</sub> receptor negative alloster ...[more]

PMID: 36402243

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Project description:<h4>Background</h4>Despite the revolutionary success of chimeric antigen receptor (CAR) therapy in hematologic malignancies, its application in solid tumors is hindered by the scarcity of tumor-specific membrane antigens rigorously validated in clinical specimens. Here, we identified glutamate metabotropic receptor 4 (GRM4) as a novel target with dual advantages: breast cancer (BC)-predominant membrane expression and restricted normal tissue distribution, potentially circumventing on-target off-tumor toxicity.<h4>Methods</h4>Through integrative multi-database analysis (DESeq2/edgeR/limma differential screening, CellMarker filtration, the Human Protein Atlas database validation), GRM4 was prioritized. Its expression was validated in non-malignant organs [immunohistochemistry (IHC)], BC cell lines [western blot (WB)/quantitative polymerase chain reaction (qPCR)/immunofluorescence (IF)], 158 BC clinical samples with paired para-cancerous tissues (IHC). Subcellular localization, tumor proportion score, and subtype-specific distribution were analyzed. Clinical correlations and survival outcomes were evaluated using chi-square tests and Kaplan-Meier analysis.<h4>Results</h4>Membrane expression was confirmed by IHC in 35.44% of clinical cases, and its presence in breast cancer cell lines was validated by WB, qPCR, and IF. GRM4 exhibited tumor-specific membrane/cytoplasmic expression in 80.38% of BC patients (127/158) across all subtypes (≥70% positivity), with 51.27% showing >50% tumor cell positivity. Critically, GRM4 was absent in normal breast/para-cancerous tissues and confined to the brain in non-malignant organs. While GRM4 correlated with advanced clinical stage (p=0.025) and age (p=0.026), it was independent of overall survival (p=0.449).<h4>Conclusions</h4>GRM4 emerges as a novel CAR-associated target for breast cancer, demonstrating tumor-specific overexpression, brain-restricted normal expression, and pan-subtype applicability with potential on-target off-tumor effect.

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Metabotropic glutamate receptor 3 as a potential therapeutic target for psychiatric and neurological disorders.

Publications

Metabotropic glutamate receptor 3 as a potential therapeutic target for psychiatric and neurological disorders.

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