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Abstract
Metabotropic glutamate receptor 1 (mGlu1) is a G protein-coupled receptor which enhances the hydrolysis of membrane phosphoinositides (PI). Additionally, mGlu1 receptors have been shown to stimulate cytoprotective signaling in the presence of the endogenous ligand glutamate. This goal of the experiments in the following thesis was to (1) characterize the signal transduction pathway through which mGlu1 receptors protect cells expressing these receptors from toxicity. Instead of the classical G protein-mediated (PI) signaling, the following experiments indicate that mGlu1a receptors cause a sustained phosphorylation of ERK that is β-arrestin-1 dependent. This G protein-independent signaling pathway was necessary for protective signaling and was stimulated by glutamate, but not quisqualate, demonstrating ligand bias at this receptor. (2) Therefore, pharmacological and mutational studies were carried out to investigate the molecular basis of this ligand bias. Together, these studies indicate the existence of 3 classes of mGlu1a receptor agonists: (a) unbiased agonists, such as glutamate, which stimulate both signal transduction pathways, (b) biased agonists, such as quisqualate, which only stimulate PI hydrolysis, and (c) agonists which are biased toward sustained ERK phosphorylation and protective signaling. In these studies, glutaric and succinic acid were identified as protection-biased mGlu1a receptor agonists. Further pharmacological studies indicate that quisqualate does not inhibit glutamate-induced protection and glutaric acid fails to inhibit glutamate-induced PI hydrolysis, suggesting the existence of two distinct, non-overlapping agonist binding sites on mGlu1a receptors.
