Protection Against Oxidative Glutamate Toxicity Mediated by the Mouse (Mus musculus) Orphan Receptor GPR39

Abstract

The aim of this study was to demonstrate protecion against oxidative glutamate toxicity by G-protein coupled receptors, and to characterize the mechanism of protection mediated in particular by the mouse orphan receptor, GPCR mGPR39. To begin with, the influence of the cell culture conditions on glutamate-induced death was investigated. The results implied that HT22 cells, depending on cell density, modify the growth medium protecting other cells in the vicinity from glutamate-induced cell death.

Furthermore, the inherent differences between a glutamate-sensitive and resistan cell line were used, by virtue of contrast, to analyze the role of G-protein coupled signaling pathways in this paradigm. The results of these initial experiments led to the investigation of orphan receptors, identifying new receptors possibly involved in glutamate-induced oxidative toxicity. These receptors were futher tested using toxicity assays and the receptor offering the greatest apparent protection, namely, mGPR39, was chosen for further analysis.

In order to understand its role during the development, in situ hybridizations were carried out. To understand its role in glutamate toxicity, stable cells overexpressing the receptor were generated and analyzed. Moreover, a possible role of mGPR39 in another disease was investigated.