Molecular mechanisms that desensitize metabotropic glutamate receptor signaling: An overview

Abstract

The purpose of the present article is to review our actual knowledge on the desensitization of metabotropic glutamate receptors based on the literature available so far, with the attempt to emphasize all converging data and to give a possible explanation to those evidences that still remain controversial. 1. We review our knowledge on the regulation of mGlu receptors based on the available literature 2. We report converging data and we comment on issues that still remain controversial.

This article is part of a Special Issue entitled ‘Metabotropic Glutamate Receptors’.

Introduction

Receptor responsiveness is regulated at the level of the G-protein coupled receptors (GPCR) by a process termed desensitization. This involves a combination of events including receptor phosphorylation by different kinases, internalization and interaction with specific regulatory proteins. Receptor homologous desensitization is a “feedback” mechanism that protects against both acute and chronic receptor over-stimulation and occurs shortly after exposure of GPCR to agonists (Liggett, 2011). In the process of homologous desensitization, G-coupled receptor kinases (GRKs) were initially identified as serine/threonine kinases that, acting in concert with their functional partner arrestins, regulate the activity of most GPCR (recently reviewed by Penela et al., 2010). The GRKs, a family of seven members in mammals, phosphorylate the agonist-occupied receptor. Arrestin then binds to the phosphorylated receptor, which in turn uncouples from heterotrimeric G-proteins and becomes desensitized (Penela et al., 2003; Premont and Gainetdinov, 2007). Phosphorylated receptors are then targeted to clathrin-coated vesicles, where they are resensitized and recycled back to plasma membranes (Reiter and Lefkowitz, 2006; Moore et al., 2007). Besides this “classical paradigm”, emerging evidence indicates that both GRKs and arrestins actively participate to signal propagation. They can interact with proteins involved in signal transduction, driving the signal and finely modulating the cellular responses to GPCR activation. The potential for GRKs to interact with different proteins is predicted by their molecular structure, which clearly indicates that these are multi-domain proteins. All GRKs share a highly conserved catalytic domain; in the βARK subfamily (which includes GRK2 and GRK3), this catalytic domain is flanked by an N-terminal domain and by a C-terminal domain. The N-terminal domain is important for receptor recognition, for intracellular membrane anchoring, and also contains an RH domain (regulator of G protein signaling (RGS) homology domain) which enables GRK2 and GRK3 to specifically interact with Gαq family members, thus blocking their interaction with their effector, phospholipase C beta (PLCβ). In the C-terminal region, GRK2 and GRK3 contain a pleckstrin homology domain (PH) that allows the interaction with the phosphatidylinositol 4,5-bisphosphate and free Gβγ subunits (Penela et al., 2010). It has been documented in several studies that GRK2 has a wide pattern of interacting proteins, ranging from GPCR, tyrosine kinase receptors such as PDGF-Rβ (Hildreth et al., 2004), to non-receptor substrates such as tubulin, synucleins, phosducin, ribosomal protein P2, the ERM family protein ezrin, the calcium-binding protein DREAM, IκBα or the p38 MAPK (Peregrin et al., 2006; Patial et al., 2009). Different studies have documented that β-arrestins act as scaffold proteins bringing to the receptors signaling molecules such as src, the phosphodiesterase PDE4, components of the MAPK cascade, components of the NFκB cascade and many others (reviewed in Reiter and Lefkowitz, 2006; Premont and Gainetdinov, 2007; DeWire et al., 2007).

Metabotropic glutamate (mGlu) receptors belong to class C of the GPCR superfamily. Similar to all GPCRs, mGlu receptors contain a heptahelical domain in the membrane region and they share with other members of class C GPCRs an extended extracellular N-terminal domain in which the binding region for glutamate is located. The 8 subtypes identified are classified into 3 groups based on amino-acid sequence, transduction mechanisms and pharmacological profile. Group I includes mGlu1 and mGlu5 receptors, which are coupled to Gq and activate phospholipase C-β (PLCβ). mGlu1 and mGlu5 receptors are mainly found in the peripheral portions of postsynaptic elements, where they modulate excitatory synaptic transmission and synaptic plasticity. Group II (mGlu2 and mGlu3) and Group III (mGlu4, mGlu6 mGlu7 and mGlu8) mGlu receptors are coupled to Gi/Go and negatively regulate adenylyl cyclase activity. All these receptor subtypes, with the exception of mGlu6, are preferentially localized on presynaptic terminals, where they inhibit neurotransmitter release (see Nicoletti et al., 2011 for a recent review). As the mGlu receptors have a significant similarity in overall structure, it sounds interesting to study the desensitization of these receptors, in order to establish the molecular determinants that drive their signal transduction towards specific cellular responses. The characterization of these mechanisms and their regulation might be important for the pathophysiology of the diseases in which mGlu receptors are known to be involved.

The purpose of the present article is to review our knowledge on the desensitization of mGlu receptors based on the literature available so far, with the attempt to emphasize all converging data and to comment on issues that still remain controversial.