title: Dual neurotoxic and neuroprotective role of metabotropic glutamate receptor 1 in conditions of trophic deprivation - possible role as a dependence receptor.
abstract: Group I metabotropic glutamate receptors have been often implicated in various models of neuronal toxicity, however, the role played by the individual receptors and their putative mechanisms of action contributing to neurotoxicity or neuroprotection remain unclear. Here, using primary cultures of rat cerebellar granule cells and mouse cortical neurons, we show that conditions of trophic deprivation increased mGlu1 expression which correlated with the developing cell death. The inhibition of mGlu1 expression by specific siRNA attenuated toxicity, while adenovirus-mediated overexpression of mGlu1 resulted in increased cell death, indicating a causal relationship between the level of receptor expression and neuronal survival. In pharmacological experiments selective mGlu1 antagonists failed to protect from mGlu1-induced cell death, instead, neuronal survival was promoted by glutamate acting at mGlu1 receptors. Such properties are characteristics of a novel heterogeneous family of dependence receptors which control neuronal apoptosis. Our findings indicate that increased expression of mGlu1 in neurons creates a state of cellular dependence on the presence of its endogenous agonist glutamate. We propose a new role and a new mechanism for mGlu1 action. This receptor may play a crucial role in determining the fate of individual neurons during the development of the nervous system.
authors.affiliation: Department of Pharmacology, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington, DC 20057, United States.
authors.forename: Sergey
authors.initials: S
authors.lastname: Pshenichkin
authors.forename: Monika
authors.initials: M
authors.lastname: Dolińska
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Klauzińska
authors.forename: Victoria
authors.initials: V
authors.lastname: Luchenko
authors.forename: Ewa
authors.initials: E
authors.lastname: Grajkowska
authors.forename: Jarda T
authors.initials: JT
authors.lastname: Wroblewski
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D002540:Cerebral Cortex / Q000166:cytology; D002867:Chromones / Q000494:pharmacology; D004148:Dioxolanes / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D018698:Glutamic Acid / Q000633:toxicity*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D011189:Potassium Chloride / Q000633:toxicity*; D011687:Purines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000502:physiology*; D013997:Time Factors; D014162:Transfection
chemical_list: C117789:7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester; D002867:Chromones; D004148:Dioxolanes; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D036341:Intercellular Signaling Peptides and Proteins; D011687:Purines; D011725:Pyridines; D034741:RNA, Small Interfering; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; C104068:4-(2-amino-6-chloro-9H-purin-9-yl)-1,3-dioxolane-2-methanol; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D011189:Potassium Chloride; C121465:6-methyl-2-(phenylethynyl)pyridine