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

Abstract

Metabotropic glutamate receptor 1 (mGlu1) is a G proteincoupled receptor that enhances the hydrolysis of membrane phosphoinositides. In addition to its role in synaptic transmission and plasticity, mGlu1 has been shown to be involved in neuroprotection and neurodegeneration. In this capacity, we have reported previously that in neuronal cells, mGlu1a exhibits the properties of a dependence receptor, inducing apoptosis in the absence of glutamate, while promoting neuronal survival in its presence (Pshenichkin, S., Dolińska, M., Klauzińska, M., Luchenko, V., Grajkowska, E., and Wroblewski, J. T. (2008) Neuropharmacology 55, 500 -508). Here, using CHO cells expressing mGlu1a receptors, we show that the protective effect of glutamate does not rely on the classical mGlu1 signal transduction. Instead, mGlu1a protective signaling is mediated by a novel, G protein-independent, pathway which involves the activation of the MAPK pathway and a sustained phosphorylation of ERK, which is distinct from the G protein-mediated transient ERK phosphorylation. Moreover, the sustained phosphorylation of ERK and protective signaling through mGlu1a receptors require expression of ␤-arrestin-1, suggesting a possible role for receptor internalization in this process. Our data reveal the existence of a novel, noncanonical signaling pathway associated with mGlu1a receptors, which mediates glutamate-induced protective signaling. Metabotropic glutamate (mGlu)3 receptors are a family of G protein-coupled receptors (GPCRs) that have been categorized into three groups based on sequence homology and pharmacology (2, 3). Structural features of these receptors include a large extracellular domain containing an agonist binding site (4), seven transmembrane-spanning domains, and a variable length intracellular C-terminal domain. The second intracellular loop and portions of the C terminus are responsible for binding of G proteins and therefore for the coupling of mGlu receptors to the different second messenger systems (5, 6). Group I mGlu receptors stimulate phospholipase C (PLC) via coupling to G q/11 (7,8), which results in the hydrolysis of membrane phosphoinositides (PI) followed by increased Ca 2ϩ release from intracellular stores. Furthermore, agonist stimulation of group I mGlu receptors more recently has been shown to cause a transient phosphorylation of extracellular signal-regulated kinase (ERK) (9, 10).Several studies indicate that activation of group I mGlu receptors promotes neuronal death. Such results have been demonstrated in an in vivo model of rat traumatic brain injury and in an in vitro model of traumatic injury of rat cortical neurons (11). Toxic effects of group I mGlu receptors appear to be mediated through mechanisms including the activation of protein kinase C (12) and potentiation of NMDA and AMPA currents (13-16). In contrast, several other studies indicate that in the presence of glutamate, mGlu1 induces signaling that facilitates growth and development as opposed to neurotoxicity. When stimulated with glutamate, mGlu1 ...

Ligand Bias at Metabotropic Glutamate 1a Receptors: Molecular Determinants That Distinguish β-Arrestin-Mediated from G Protein-Mediated Signaling

“…Our previous study on signal transduction of mGlu1a receptors indicated that classic, G protein-mediated, signal transduction and transient ERK phosphorylation differed in their pharmacological profiles from sustained ERK phosphorylation and protective signaling; classic mGlu1a receptor-mediated PI hydrolysis and transient ERK phosphorylation were induced by both quisqualate and glutamate, with quisqualate being the most potent agonist (Emery et al, 2010). These data are consistent with several previous reports on the pharmacological features of mGlu1 receptormediated PI hydrolysis (Aramori and Nakanishi, 1992) and ERK phosphorylation (Thandi et al, 2002).…”

“…Therefore, the mGlu1 receptor exhibits the properties of a dependence receptor (Pshenichkin et al, 2008), inducing apoptosis in the absence of glutamate and promoting neuronal survival in its presence. In CHO cells transfected with mGlu1a receptors, stimulation of the receptors with glutamate protected cells from serum withdrawalinduced apoptosis (Emery et al, 2010). In this model, protective signaling through mGlu1a receptors was accomplished through ␤-arrestin-1-dependent sustained phosphorylation of ERK (Emery et al, 2010).…”

“…In CHO cells transfected with mGlu1a receptors, stimulation of the receptors with glutamate protected cells from serum withdrawalinduced apoptosis (Emery et al, 2010). In this model, protective signaling through mGlu1a receptors was accomplished through ␤-arrestin-1-dependent sustained phosphorylation of ERK (Emery et al, 2010).…”

“…Group I mGlu receptors (mGlu1 and mGlu5 receptors) stimulate phospholipase C (PLC) through coupling to G q/11 (Aramori and Nakanishi, 1992), which results in the hydrolysis of membrane phosphoinositides (PIs), followed by increased Ca 2ϩ release from intracellular stores. Stimulation of group I mGlu receptors also was shown to cause phosphorylation of extracellular signalregulated kinase (ERK), both in a transient, PLC-dependent manner (Choe and Wang, 2001;Karim et al, 2001) and in a sustained, G protein-independent, ␤-arrestin-dependent manner (Emery et al, 2010).…”

Somatic Mutations in GRM1 in Cancer Alter Metabotropic Glutamate Receptor 1 Intracellular Localization and Signaling

“…Group I mGluRs (mGluR1a and mGluR5) couple primarily through Gaq and also activate G protein-independent signal transduction pathways, including mitogen-activated kinases. Group I mGluR-mediated ERK1/2 activation can occur via protein kinase C (PKC), b-arrestin, nonreceptor tyrosine kinases, such as Src and Pyk2, and Homer (Thandi et al, 2002;Mao et al, 2005;Emery et al, 2010;Nicodemo et al, 2010).…”