Activation of group-I metabotropic glutamate receptor reduces stress granules formation through a mechanism mediated by FMRP.

AIMS. Fragile X Mental Retardation Protein (FMRP) is an RNA binding protein involved in RNA metabolism and protein synthesis; its lack causes Fragile X syndrome, a common form of inherited intellectual disability and autism. FMRP is associated with the pool of mRNAs that are recruited and protected into stress granules (SGs) upon cellular stress, during which constitutive protein synthesis is blocked. Group-I metabotropic glutamate receptors (mGluRs) stimulate FMRP-mediated RNA transport and protein synthesis, but their role in SGs formation is unknown. METHODS. Cultured astrocytes from wild type (WT) and Fmr1 knockout (KO) mice were exposed to sodium arsenite (NaAsO2, 200-500 µM, 30-90 minutes) with/without a pre-treatment with the group-I mGluR selective agonist DHPG (100 uM, 5 minutes). Immunocytochemistry for TIA-1 was used to detect SGs and the FMRP recruitment in SGs; phosphorylation of eIF2? and FMRP was examined by Western blot. RESULTS. We observed an increased number of cells with SGs after exposure to NaAsO2, as expected; however, this effect was much lower in KO than WT astrocytes. In WT cultures the activation of mGluRs before stress reduced SGs formation, TIA-1/FMRP co-localization in SGs, and eIF2?- and FMRP-phosphorylation. In contrast, mGluR activation had no effect in KO astrocytes. CONCLUSIONs. FMRP plays a key role in SGs formation. mGluR activation affects SGs formation through a FMRP-mediated mechanism. Since phosphorylation of eIF2? initiates SGs formation and phosphorylated-FMRP is crucial for FMRP-mediated inhibition of protein synthesis, mGluRs may act by shifting the balance from inhibition to activation of protein synthesis during stress.