The trick of the tail: protein–protein interactions of metabotropic glutamate receptors

Abstract

It was initially believed that G-protein-coupled receptors, such as metabotropic glutamate receptors, could simply be described as individual proteins that are associated with intracellular signal cascades via G-proteins. This view is no longer tenable. Today we know that metabotropic glutamate receptors (mGluRs) can dimerize and bind to a variety of proteins in addition to trimeric G-proteins. These newly identified protein interactions led to the discovery of new regulatory mechanisms that are independent of and sometimes synergistic with the classical G-protein-coupled second messenger pathways. Notably, several of these mechanisms connect mGluR-mediated signaling to other receptor classes, thereby creating a network of different receptor types and associated signal cascades. The intracellular C-termini of mGluRs play a key role in the regulation of these networks, and various new protein interactions of these domains were described recently. Because mGluRs are involved in a variety of physiological and pathophysiological processes, some of the proteins interacting with this receptor class have potential as valuable pharmaceutical targets. This review will give a comprehensive overview of proteins interacting with mGluR C-termini, highlight new evolving regulatory mechanisms for glutamatergic signal transduction and discuss possibilities for future drug development.

Band 4.1 proteins are expressed in the retina and interact with both isoforms of the metabotropic glutamate receptor type 8

“…If the same holds true for mGluR8 expressed in photoreceptors, binding of 4.1B to mGluR8 C-termini might not directly compete with interacting G-proteins, but either change their binding affinity for a distant site, or influence the binding of other mGluR8 interactors. Indeed, mGluR8a/b C-termini contain binding sites for a large number of interacting proteins that partly overlap with the identified stretch of four basic amino acids proposed to be important for 4.1B binding (Enz 2007).…”

“…Similar to our findings, co-expression of 4.1G with mGluR1a or the A1 adenosine receptor increases their surface membrane localization and inhibits G-protein signaling (Lu et al 2004a,b;Tateyama and Kubo 2007). In principal, band 4.1 proteins could inhibit G-protein signaling by (i) changing the affinity of the ligand-binding pocket of receptors, (ii) changing the affinity of G-protein binding sites in their intracellular domains, (iii) completely blocking second messenger pathway by preventing Gproteins from interacting, or (iv) regulating the binding of additional mGluR8 interactors (Enz 2007). Which of these possibilities hold true for amacrine, ganglion and horizontal cells is only speculative at the moment, because neither domains of mGluR8a/b involved in G-protein signaling, nor mGluR8a/b binding G-protein types are known in these neurons.…”

“…By this means, mGluR binding partners are important regulators for glutamatergic neurotransmission. In recent years, several proteins interacting with mGluR C-termini were identified, such as enzymes, scaffold and cytoskeleton proteins (Enz 2007). Interactors of mGluR8 C-termini include Calmodulin (El Far et al 2001), PICK1 (El Far et al 2000), Filamin-A (Enz 2002) and proteins of the sumoylation cascade (Tang et al 2005).…”

The ins and outs of syntenin, a multifunctional intracellular adaptor protein

“…Glutamate is the principle excitatory neurotransmitter in the CNS and regulates multiple signal-transduction cascades as well as synapse excitability via mechanisms that are located at both preand post-synaptic membranes. Fast excitatory responses are regulated via three major classes of ionotropic receptors, and syntenin can associate with an array of these receptors, including the AMPA (an artificial glutamate analogue)-type glutamate receptors GluR1-GluR4, kainate receptors GluR5 2b , GluR 2c and GluR6, and metabotropic receptors mGluR4a, mGLuR6, mGluR7a and mGluR7b (Enz and Croci, 2003;Hirbec et al, 2002;Hirbec et al, 2003;Enz, 2007). The kainate receptors GluR5 and GluR6 are present at both pre-and post-synaptic membranes, and are highly expressed early in development.…”

Calmodulin dynamically regulates the trafficking of the metabotropic glutamate receptor mGluR5

“…Most of the binding sites for these protein-protein interactions reside within the long intracellular C-terminal domain of mGluR5, suggesting that this region is critical in the functional regulation of mGluR5. For example, the Homer proteins bind to the PPxxFR motif within the distal C terminus, the Tamalin protein associates with the distal C terminus, and calmodulin (CaM) and the E3 ligase Siah-1A bind to the first one-third of the mGluR5 C terminus (12)(13)(14)(15). However, the dynamic regulation of these protein-protein interactions has not been described.…”