Regulation of metabotropic glutamate receptor signaling, desensitization and endocytosis

Metabotropic glutamate receptors (mGluRs) comprise a unique family of G protein-coupled receptors (GPCR) that can be classified into 3 groups based on G protein coupling specificity and sequence similarity. Group I mGluRs (mGluR1 and mGluR5) are coupled to the heterotrimeric G protein Gαq/11 and trigger the release of calcium from intracellular stores. In the present review, we discuss the molecular mechanisms involved in the desensitization and endocytosis of group I mGluRs. Group I mGluRs desensitize in response to both second-messenger-dependent protein kinases and G protein-coupled receptor kinases (GRK). However, GRK2-mediated mGluR1 desensitization appears to be both phosphorylation- and β-arrestin-independent. In addition to GRK-mediated uncoupling of mGluRs from heterotrimeric G proteins, the huntingtin-interacting protein, optineurin, also contributes to mGluR1 and mGluR5 desensitization. The G protein-uncoupling activity of optineurin appears to be facilitated by the presence of polyglutamine-expanded mutant huntingtin but not wild-type huntingtin. Group I mGluRs also undergo both agonist-dependent and -independent endocytosis in both heterologous cell expression systems and primary neuronal cultures. The present review overviews the current understanding of the contribution of second messenger-dependent protein kinases, β-arrestins and a novel Ral/phospholipase D2 (PLD2)-mediated endocytic pathway to the regulation of Group I mGluR endocytosis. Overall, the regulation of Group I mGluR desensitization and endocytosis appears to be mediated by the same molecular intermediates as have been described for more typical GPCR such as the β2-adrenergic receptor. However, there appears to be subtle, but important, differences in the mechanisms by which these intermediates are employed to regulate Group I mGluR desensitization and endocytosis.