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 characteristic 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.

The Protective Signaling of Metabotropic Glutamate Receptor 1 Is Mediated by Sustained, β-Arrestin-1-dependent ERK Phosphorylation

“…In a previous report, we have shown that glutamate, acting selectively at mGlu1 receptors, protects neurons from apoptotic death induced by trophic deprivation (1). In this study, we show the existence of a novel signal transduction mechanism that allows mGlu1 receptors to mediate this protective signaling.…”

“…This mechanism appears to be responsible for the protective action of glutamate mediated by mGlu1a receptors. We have proposed previously that mGlu1a may function as a dependence receptor causing apoptosis in the absence of glutamate, possibly due to the cleavage of its C-terminal domain (1). Now, we propose that the protective, positive signaling of mGlu1, which occurs in the presence of glutamate, is mediated by this new, G protein-independent, mechanism of signal transduction.…”

“…Protective Effects of Glutamate-Our previous studies in primary cultures of cortical and cerebellar neurons have shown that glutamate, acting selectively at mGlu1a receptors, rescued these neurons from apoptotic cell death induced by conditions of trophic deprivation (1). This protective effect of glutamate was revealed in the presence of antagonists of ionotropic glutamate receptors, which suppressed the excitotoxic actions of glutamate.…”

“…When stimulated with glutamate, mGlu1 has been shown to stimulate axon migration in the developing CNS (17) and outgrowth of dendritic spines in the developing hippocampus (18). We have described recently that mGlu1a produces dual neuroprotective and neurotoxic signaling in cerebellar and cortical neurons (1). Thus, mGlu1a exhibits the properties of a dependence receptor (19,20), inducing apoptosis in the absence of glutamate, while promoting neuronal survival in its presence.…”

Monitoring Neuroprotective Effects Using Positron Emission Tomography With [ 11 C]ITMM, a Radiotracer for Metabotropic Glutamate 1 Receptor

“…3 Recent results suggest that blockade of the mGlu1 receptor may provide an effective approach for inhibiting glutamatemediated neurotoxicity in the ischemic brain. 4 Furthermore, some mGlu1 antagonists have shown a neuroprotective effect in the ischemic brain. 4,5 However, cerebral infarction volumes after ischemia in mGlu1-knock-out mice were not different from those in wild-type mice.…”