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Associate editor: P. Molenaar Regulation of metabotropic glutamate receptor signaling,

Summary: Associate editor: P. Molenaar
Regulation of metabotropic glutamate receptor signaling,
desensitization and endocytosis
Gurpreet K. Dhami, Stephen S.G. Ferguson
Cell Biology Research Group, Robarts Research Institute, London, Ontario, Canada N6A 5K8
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1
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 Gq/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 -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, -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 2-adrenergic receptor. However, there appears to be subtle, but important, differences in the mechanisms by which these


Source: Alford, Simon - Department of Biological Sciences, University of Illinois at Chicago


Collections: Biology and Medicine