Conserved estrogen binding and signaling functions of the G protein-coupled estrogen receptor 1 (GPER) in mammals and fish

Abstract

Recent studies by several research groups have shown that G-protein estrogen receptor-1, GPER, formerly known as GPR30, mediates 17β-estradiol (E2) activation of signal transduction pathways in a variety of human cancer cells and displays E2 binding typical of a membrane estrogen receptor. However, the importance of GPER as an estrogen receptor has been questioned by Otto and coworkers. Some of the pitfalls in investigating the functions of recombinant steroid membrane receptors that may explain the negative results of these investigators are discussed. The characteristics of GPER have also been investigated in a teleost fish, Atlantic croaker, where it has been shown to mediate E2 inhibition of oocyte maturation. Investigations on newly discovered homologous proteins from distantly-related vertebrate groups are valuable for determining their fundamental, evolutionarily-conserved functions. Therefore, the functions of croaker and human GPERs were compared. The comparisons show that croaker and human GPER have very similar estrogen binding characteristics, typical of estrogen membrane receptors, and activate the same estrogen signaling pathways via stimulatory G proteins (Gs) resulting in increased cAMP production. These results suggest that the estrogen binding and estrogen signaling functions of GPER arose early in vertebrate evolution, prior to the divergence of the teleosts from the tetrapods, more than 200 million years ago. The finding that estrogen membrane signaling through GPER has been conserved for such a long period in two distantly-related vertebrate groups, mammals and fish, suggests that this is a fundamental function of GPER in vertebrates, and likely its major physiological role.

Rapid steroid hormone actions initiated at the cell surface and the receptors that mediate them with an emphasis on recent progress in fish models

“…In addition, several functional motifs have been identified on nuclear receptors which are of potential importance in their membrane expression and intracellular signaling [81,182,222,260,262]. Although considerable progress has been made in the past few years, the functional characterization of mPRs, GPR30 and membrane–bound nuclear steroid receptors is incomplete, and there is considerable controversy over their importance in mediating nonclassical steroid actions [104,107,155,210,212,261]. …”

Expression of G protein estrogen receptor (GPER) on membrane of mouse oocytes during maturation

“…In addition to these classic genomic actions by activation of nuclear estrogen receptor (nER) and resulting in changes of transcription rates of a large number of estrogen-responsive genes, some estrogen receptors associated with the cell surface membrane and can be rapidly activated by exposure of cells to estrogen through nongenomic estrogen actions [1,2]. Several cell and tissue models have been found in hypothalamic neurons, pancreatic islets, marophages, and human breast cancer cells, are not involved in nER but mediated by novel membrane estrogen receptor (mER) [3][4][5][6].…”

Testosterone rapidly increases ejaculate volume and sperm density in competitively breeding goldfish through an estrogenic membrane receptor mechanism

“…Such rapid effects do not easily fit within the classic model of hormonal regulation, in which steroids modify gene expression over the course of hours to days. Instead, non-transcriptional mechanisms involving activation of estrogen receptors (Razandi et al, 1999;Wade et al, 2001) or G protein-coupled receptors (Thomas et al, 2010) located on the plasma membranes of target cells are thought to underlie several of the behavioral changes that occur over the short time scales that characterize reproductive encounters in these species. Whether and how similar steroid receptor mechanisms may also rapidly influence reproductive physiology and/or modulate ejaculation is unknown, however, this is an important issue to address, especially in competitively breeding species, because processes such as the rates of sperm production, storage, and release play a critical role in sperm competition and reproductive success in multi-male mating environments.…”