The Role of Extracellular Signal-Regulated Kinases (ERK) in the Regulation of mGlu5 Receptors in Neurons

Abstract

The metabotropic glutamate (mGlu) receptor 5 is a G protein-coupled receptor and is densely expressed in the mammalian brain. Like other glutamate receptors, mGlu5 receptors are tightly regulated by posttranslational modifications such as phosphorylation, although underlying mechanisms are incompletely investigated. In this study, we investigated the role of a prime kinase, extracellular signal-regulated kinase 1 (ERK1), in the phosphorylation and regulation of mGlu5 receptors in vitro and in striatal neurons. We found that recombinant ERK1 proteins directly bound to the C-terminal (CT) tail of mGlu5 receptors in vitro. Endogenous ERK1 also interacted with mGlu5 receptor proteins in adult rat striatal neurons in vivo. The kinase showed the ability to phosphorylate mGlu5 receptors. A serine residue in the distal region of mGlu5 CT was found to be a primary phosphorylation site sensitive to ERK1. In functional studies, we found that pharmacological inhibition of ERK with an inhibitor U0126 reduced the efficacy of mGlu5 receptors in stimulating production of cytoplasmic inositol-1,4,5-triphosphate, a major downstream conventional signaling event, in striatal neurons under normal conditions. These results identify mGlu5 as a new biochemical substrate of ERK1. The kinase can interact with and phosphorylate an intracellular domain of mGlu5 receptors in striatal neurons and thereby control its signaling efficacy.

Group I Metabotropic Glutamate Receptors and Interacting Partners: An Update

“…Given that S1126 resides within the highly conserved Homer binding motif on mGlu5 (rat: 1123TPPSPF), phosphorylation of S1126 as well as T1123 exerts a significant impact on the Homer-mGlu1/5 binding. Consistently, recombinant ERK1 was recently confirmed to directly bind to mGlu5 CT in vitro, and endogenous ERK1 and mGlu5 formed complexes in rat striatal neurons enriched with mGlu5 receptors [22]. Under basal conditions, the ERK1-mediated mGlu5 phosphorylation appears to be critical for mGlu5 signaling to IP 3 production [22].…”

“…Consistently, recombinant ERK1 was recently confirmed to directly bind to mGlu5 CT in vitro, and endogenous ERK1 and mGlu5 formed complexes in rat striatal neurons enriched with mGlu5 receptors [22]. Under basal conditions, the ERK1-mediated mGlu5 phosphorylation appears to be critical for mGlu5 signaling to IP 3 production [22].…”

Metabotropic Glutamate Receptor Trafficking and its Role in Drug-Induced Neurobehavioral Plasticity

“…It should be noted that both groups I and group II/III receptors can also modulate G-protein independent signaling pathways [25,26], adding additional complexity to mGlu-dependent regulation of cellular signaling and synaptic plasticity. Emerging evidence suggests that these non-canonical signaling pathways can also provide feedback regulation of mGlu function through post-translational modification and trafficking [27][28][29][30][31]. While the dysregulation of mGluRs has been linked to a variety of neurological and psychiatric disorders, the role of mGluR membrane trafficking in these disorders remains poorly understood.…”