Crosstalk between nuclear and G protein-coupled estrogen receptors

Abstract

In 2005, two groups independently discovered that the G protein-coupled receptor GPR30 binds estradiol in cultured cells and, in response, initiates intracellular signaling cascades Revankar et al. (2005), Thomas et al. (2005). GPR30 is now referred to as GPER, the G-protein coupled estrogen receptor Prossnitz and Arterburn (2015). While studies in animal models are illuminating GPER function, there is controversy as to whether GPER acts as an autonomous estrogen receptor in vivo, or whether GPER interacts with nuclear estrogen receptor signaling pathways in response to estrogens. Here, we review the evidence that GPER acts as an autonomous estrogen receptor in vivo and discuss experimental approaches to test this hypothesis directly. We propose that the degree to which GPER influences nuclear estrogen receptor signaling likely depends on cell type, developmental stage and pathology.

Figure 1. Estrogen receptor alpha (ERα) splice variants

Depicted protein structures of full length and spice variants in human (h), mouse (m), zebrafish (z), killifish (k) and sea bream (sb). Functional regions (based on Krust et al, EMBO J 1986): AF-1, activating function 1 domain; DBD, DNA binding domain; LBD, ligand binding domain; AF-2, activating function 2 domain. Blank regions indicate amino acid sequence unique to the splice variant, except for kfERα_L∆6 and kfERα_S∆6 where the sequence following the E domain is identical. NTERP, N terminally truncated ER protein; CTERP, C terminally truncated ER protein.

Figure 2. Models for autonomous GPER signaling versus GPER-ER signaling interactions

KO, knockout animal; GPER, G protein-coupled estrogen receptor; ER, nuclear estrogen receptor alpha or beta