Rapid signalling responses via the G protein-coupled estrogen receptor, GPER, in a hippocampal cell line

The rapid non-genomic actions of 17 beta-estradiol in multiple tissues, including the nervous system, may involve the activation of the G-protein-coupled receptor, GPER. Different signalling pathways have been suggested to be activated by GPER in different cell lines and tissues. Controversially, GPER has also been suggested to be activated by the mineralocorticoid aldosterone, and by the non-steroidal diphenylacrylamide compound, STX, in some preparations. Evidence for the ability of the GPER agonist, G-1, and for aldosterone in the presence of the mineralocorticoid receptor antagonist, eplerenone, to potentiate forskolin-stimulated cyclic AMP levels in the hippocampal clonal cell line, mHippoE-18 is reviewed. The effects of both agents are blocked by the GPER antagonist G36, by PTX, (suggesting the involvement of Gi/o G proteins), by BAPTA-AM, (suggesting they are calcium sensitive), by wortmannin (suggesting an involvement of PI3Kinase) and by soluble amyloid-beta peptides. STX also stimulates cyclic AMP levels in mHippoE-18 cells and these effects are blocked by G36 and PTX, as well as by amyloid-beta peptides. This suggests that both aldosterone and STX may be capable of activating GPER in mHippoE-18 cells. Possible molecular mechanisms that may underlie these effects are discussed, together with possible forward directions for research on rapid non-genomic signalling by GPER, emphasising the importance of understanding the spatio-temporal aspects of its signalling in various tissues.