Interaction between estrogen receptor and metabotropic glutamate receptor 1 mediates the dual effect of estrogen in neuroprotection and neurodegeneration

Estrogen receptors (ER) are known to exert important action in the central nervous system, including neuroprotection. These effects are due to interaction of estrogen with membrane localized receptors that signal through rapid transduction pathways. How membrane ERs initiate rapid signal transduction has not been clarified, but they have been reported to interact with other membrane receptors, including metabotropic glutamate receptors (mGluR). The role of estrogen in neuroprotection is not always defined and above all, neuroprotective data provided by preclinical studies have not been confirmed by the use of estrogen in humans: estrogen treatment can in fact be neuroprotective but also responsible for increased neurodegeneration. The dual role ascribed to estrogen, can be observed also with mGluR1 agonists. 3,5-Dihydroxyphenylglycine (DHPG) behaves both as a neuroprotective and neurodegenerative factor. The aim of this study has been to point out whether the similar behaviour of the estrogen and mGlu1R agonists depends on the interaction between their receptors. Neuroprotective activity of both drugs was demonstrated in an in vitro model of cortical cultures exposed to beta amyloid (Aâ) toxicity. Pre-treatment with either 17â-estradiol (E2) and DHPG reduced Aâ-induced neuronal death. The neuroprotective effect was due to strict interaction between mGluR1 and ERá, as treatment with the mGluR1 antagonist, JNJ 16259685, or ER antagonist, ICI 182,780, prevented the effect induced by the respective as well as by the reciprocal agonist. Moreover, E2 and DHPG shared a common signalling pathway, as they stimulated to a similar extent phosphoinositide hydrolysis and induced enhanced phosphorylation of AKT. Both these effects were not additive, when the two agonists were added together and they were prevented by the reciprocal antagonists. In addition, a similar effect was reproduced when each receptor was expressed in recombinant cells. The interaction between the two receptors seems to be involved also in the ...