Membrane-localised oestrogen receptor alpha and beta influence neuronal activity through activation of metabotropic glutamate receptors

Abstract

Until recently, the idea that oestradiol could affect cellular processes independent of nuclear oestrogen receptors (ERs) was controversial. This was despite the large number of carefully controlled studies performed both within and outside the nervous system demonstrating that oestrogens regulate various intracellular signalling pathways by acting at the membrane surface of cells and/or at biological rates incompatible with the time course of genomic-initiated events. At present, it is far less controversial that oestradiol acts at surface membrane receptors to regulate nervous system function. Recent studies have demonstrated that the classical intracellular ERs, ERalpha and ERbeta, are major players in mediating the actions of oestradiol on the membrane surface. This review focuses on one potential mechanism by which surface-localised ERalpha and ERbeta stimulate intracellular signalling events in cells of the nervous system. After oestradiol treatment, both ERalpha and ERbeta are capable of activating different classes of metabotropic glutamate receptors (mGluRs). Oestradiol activation of mGluRs is independent of glutamate, but requires expression of several different caveolin proteins to compartmentalise the different ERs with mGluRs into functional signalling microdomains. ER/mGluR signalling is a potential means by which oestrogens can both rapidly and for extended periods, influence a variety of intracellular signalling processes and behaviours.

Fig. 1

Oestrogen receptor (ER) activation of metabotropic glutamate receptor (mGluR) signalling through interactions with caveolin proteins. (A) Model system of oestradiol-induced activation of mGluRs via caveolin-based caveolae. (B) Summary of distinct signalling pathways by which ERα and ERβ can affect cAMP response element binding protein (CREB) phosphorylation.