G-protein oestrogen receptor 1: trials and tribulations of a membrane oestrogen receptor

Oestrogens are now recognised to be able to initiate rapid, fast responses, in addition to their classical, longer-term actions. There is a growing appreciation of the potential implications of this mode of action for oestrogenic signalling in both neuronal and non-neuronal systems. As such, much effort has been made to determine the mechanisms that are critical for transducing these rapid effects into cellular responses. Recently, an orphan G-protein-coupled receptor (GPCR), termed GPR30, was identified as an oestrogen-sensitive receptor in cancer cells. This receptor, now term G-protein oestrogen receptor 1 (GPER1) has been the subject of many investigations, and a role for this receptor in the nervous system is now emerging. In this review, we highlight some of the more recent advances in our understanding of the distribution and subcellular localisation of this receptor in the brain, as well as some of the evidence for the potential role that this receptor may play in the brain. We then discuss some of the controversies surrounding the pharmacology of this receptor, and attempt to reconcile these by suggesting that the 'agonist-specific coupling' model of GPCR function may provide a potential explanation for some of the divergent reports of GPER1 pharmacology.