GPER1/GPR30 in the brain: Crosstalk with classical estrogen receptors and implications for behavior

The GPER1/GPR30 is a membrane estrogen receptor (mER) that binds 17β-estradiol (17β-E) with high affinity and is thought to play a role in cancer progression and cardiovascular health. Though widespread in the central nervous system, less is known about this receptor’s function in the brain. GPER1 has been shown to activate kinase cascades and calcium flux within cells rapidly, thus fitting in with the idea of being a mER that mediates non-genomic signaling by estrogens. Signaling from GPER1 has been shown to improve spatial memory, possibly via release of neurotransmitters and generation of new spines on neurons in the hippocampus. In addition, GPER1 activation contributes to behaviors that denote anxiety and to social behaviors such as social memory and lordosis behavior in mice. In the male hippocampus, GPER1 activation has also been shown to phosphorylate the classical intracellular estrogen receptor (ER)α, suggesting that crosstalk with ERα is important in the display of these behaviors, many of which are absent in ERα-null mice. In this review, we present a number of categories of such crosstalk, using examples from literature. The function of GPER1 as an ERα collaborator or as a mER in different tissues is relevant to understanding both normal physiology and abnormal pathology, mediated by estrogen signaling.