Physiology of membrane oestrogen receptor signalling in reproduction

The best characterised oestrogen receptors (ERs) that are responsible for membrane-initiated oestradiol signalling are the classic ERs, ERalpha and ERbeta. When in the nucleus, these proteins are oestradiol activated transcription factors but, when trafficked to the cell membrane, ERalpha and ERbeta rapidly activate protein kinase pathways, alter membrane electrical properties, modulate ion flux and can mediate long-term effects through gene expression. To initiate cell signalling, membrane ERs transactivate metabotropic glutamate receptors (mGluRs) to stimulate Gq signalling through pathways using PKC and calcium. In this review, we discuss the interaction of membrane ERalpha with metabotropic glutamate receptor 1a (mGluR1a) to initiate rapid oestradiol cell signalling and its critical roles in female reproduction: sexual behaviour and oestrogen positive feedback of the luteinising hormone (LH) surge. Although long considered to be regulated by the long-term actions of oestradiol on gene transcription, recent results indicate that membrane oestradiol cell signalling is vital for a full display of sexual receptivity. Similarly, the source of pre-ovulatory progesterone necessary for initiating the LH surge is hypothalamic astrocytes. Oestradiol rapidly amplifies progesterone synthesis through the release of intracellular calcium stores. The ERalpha-mGluR1a interaction is necessary for critical calcium flux. These two examples provide support for the hypothesis that membrane ERs are not themselves G-protein receptors; rather, they use mGluRs to signal.