Antagonists for group I mGluRs attenuate excitotoxic neuronal death in cortical cultures

Previous studies have implicated phospholipase C (PLC)-linked Group I metabotropic glutamate receptors (mGluRs) in regulating the excitability of hippocampal CA1 pyramidal neurons. We used intracellular recordings from rat hippocampal slices and specific antagonists to examine in more detail the mGluR receptor subtypes and signal transduction mechanisms underlying this effect. Application of the Group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) suppressed slow- and medium-duration afterhyperpolarizations (s- and mAHP) and caused a consequent increase in cell excitability as well as a depolarization of the membrane and an increase in input resistance. Interestingly, with the exception of the suppression of the mAHP, these effects were persistent, and in the case of the sAHP lasting for more than 1 h of drug washout. Preincubation with the specific mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), reduced but did not completely prevent the effects of DHPG. However, preincubation with both MPEP and the mGluR1 antagonist LY367385 completely prevented the DHPG-induced changes. These results demonstrate that the DHPG-induced changes are mediated partly by mGluR5 and partly by mGluR1. Because Group I mGluRs are linked to PLC via G-protein activation, we also investigated pathways downstream of PLC activation, using chelerythrine and cyclopiazonic acid to block protein kinase C (PKC) and inositol 1,4,5-trisphosphate-(IP3)-activated Ca2+ stores, respectively. Neither inhibitor affected the DHPG-induced suppression of the sAHP or the increase in excitability nor did an inhibitor of PLC itself, U-73122. Taken together, these results argue that in CA1 pyramidal cells in the adult rat, DHPG activates mGluRs of both the mGluR5 and mGluR1 subtypes, causing a long-lasting suppression of the sAHP and a consequent persistent increase in excitability via a PLC-, PKC-, and IP3-independent transduction pathway.

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NADPH Oxidase Mediates β-Amyloid Peptide-Induced Neuronal Death in Mouse Cortical Cultures

Chonnam Medical Journal ◽

10.4068/cmj.2017.53.3.196 ◽

2017 ◽

Vol 53 (3) ◽

pp. 196 ◽

Cited By ~ 12

Author(s):

Kee-Oh Chay ◽

Kyoung Young Nam Koong ◽

Shinae Hwang ◽

Jong-Keun Kim ◽

Choon Sang Bae

Keyword(s):

Nadph Oxidase ◽

Neuronal Death ◽

Amyloid Peptide ◽

Cortical Cultures ◽

Β Amyloid ◽

Β Amyloid Peptide

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Targeting the Mitochondrial Pyruvate Carrier for Neuroprotection

Brain Sciences ◽

10.3390/brainsci9090238 ◽

2019 ◽

Vol 9 (9) ◽

pp. 238 ◽

Cited By ~ 1

Author(s):

Bor Luen Tang

Keyword(s):

Parkinson’S Disease ◽

Oxidative Phosphorylation ◽

Neurodegenerative Diseases ◽

Neuronal Death ◽

Neuronal Injury ◽

Short Review ◽

Experimental Models ◽

Mitochondrial Pyruvate Carrier ◽

Neuroprotective Strategy ◽

Excitotoxic Neuronal Death

The mitochondrial pyruvate carriers mediate pyruvate import into the mitochondria, which is key to the sustenance of the tricarboxylic cycle and oxidative phosphorylation. However, inhibition of mitochondria pyruvate carrier-mediated pyruvate transport was recently shown to be beneficial in experimental models of neurotoxicity pertaining to the context of Parkinson’s disease, and is also protective against excitotoxic neuronal death. These findings attested to the metabolic adaptability of neurons resulting from MPC inhibition, a phenomenon that has also been shown in other tissue types. In this short review, I discuss the mechanism and potential feasibility of mitochondrial pyruvate carrier inhibition as a neuroprotective strategy in neuronal injury and neurodegenerative diseases.

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Energetically optimized pharmacophore modeling to identify dual negative allosteric modulators against group I mGluRs in neurodegenerative diseases

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2019.1640794 ◽

2019 ◽

Vol 38 (8) ◽

pp. 2326-2337 ◽

Cited By ~ 1

Author(s):

Sitrarasu Vijaya Prabhu ◽

Sanjeev Kumar Singh

Keyword(s):

Neurodegenerative Diseases ◽

Pharmacophore Modeling ◽

Allosteric Modulators ◽

Group I ◽

Group I Mglurs

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The post-synaptic scaffolding protein tamalin regulates ligand-mediated trafficking of metabotropic glutamate receptors

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.011979 ◽

2020 ◽

Vol 295 (25) ◽

pp. 8575-8588

Author(s):

Saurabh Pandey ◽

Namrata Ramsakha ◽

Rohan Sharma ◽

Ravinder Gulia ◽

Prachi Ojha ◽

...

Keyword(s):

Glutamate Receptors ◽

Protein Trafficking ◽

Hippocampal Neurons ◽

Metabotropic Glutamate Receptors ◽

Fragile X ◽

Critical Role ◽

Scaffolding Protein ◽

Metabotropic Glutamate ◽

Group I ◽

Group I Mglurs

Group I metabotropic glutamate receptors (mGluRs) play important roles in various neuronal functions and have also been implicated in multiple neuropsychiatric disorders like fragile X syndrome, autism, and others. mGluR trafficking not only plays important roles in controlling the spatiotemporal localization of these receptors in the cell but also regulates the activity of these receptors. Despite this obvious significance, the cellular machineries that control the trafficking of group I metabotropic glutamate receptors in the central nervous system have not been studied in detail. The post-synaptic scaffolding protein tamalin has been shown to interact with group I mGluRs and also with many other proteins involved in protein trafficking in neurons. Using a molecular replacement approach in mouse hippocampal neurons, we show here that tamalin plays a critical role in the ligand-dependent internalization of mGluR1 and mGluR5, members of the group I mGluR family. Specifically, knockdown of endogenous tamalin inhibited the ligand-dependent internalization of these two receptors. Both N-terminal and C-terminal regions of tamalin played critical roles in mGluR1 endocytosis. Furthermore, we found that tamalin regulates mGluR1 internalization by interacting with S-SCAM, a protein that has been implicated in vesicular trafficking. Finally, we demonstrate that tamalin plays a critical role in mGluR-mediated internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, a process believed to be the cellular correlate for mGluR-dependent synaptic plasticity. Taken together, these findings reveal a mechanistic role of tamalin in the trafficking of group I mGluRs and suggest its physiological implications in the brain.

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