A critical review of fundamental controversies in the field of GPR30 research

doi:10.1016/j.steroids.2009.12.006

Steroids

Volume 75, Issues 8–9, August–September 2010, Pages 603-610

https://doi.org/10.1016/j.steroids.2009.12.006 Get rights and content

Abstract

The female sex hormone estradiol plays an important role in reproduction, mammary gland development, bone turnover, metabolism, and cardiovascular function. The effects of estradiol are mediated by two classical nuclear receptors, estrogen receptor α (ERα) and estrogen receptor β (ERβ).

In 2005, G-protein-coupled receptor 30 (GPR30) was claimed to act as a non-classical estrogen receptor that was also activated by the ERα and ERβ antagonists tamoxifen and fulvestrant (ICI 182780). Despite many conflicting results regarding the potential role of GPR30 as an estrogen receptor, the official nomenclature was changed to GPER (G-protein-coupled estrogen receptor).

This review revisits the inconsistencies that still exist in the literature and focuses on selected publications that basically address the following two questions: what is the evidence for and against the hypothesis that GPR30 acts as an estrogen receptor? What is the potential in vivo role of GPR30?

Thus, in the first part we focus on conflicting results from in vitro studies analysing the subcellular localization of GPR30, its ability to bind (or not to bind) estradiol and to signal (or not to signal) in response to estradiol. In the second part, we discuss the strengths and limitations of four available GPR30 mouse models. We elucidate the potential impact of different targeting strategies on phenotypic diversity.

Section snippets

Discovery of GPR30

From 1996 to 1998, a novel G-protein-coupled receptor was cloned and reported independently by several groups [1], [2], [3], [4], [5], [6]. Names such as CMKRL2 and FEG-1 were assigned to this putative G-protein-coupled receptor reflecting the diverse research backgrounds of the involved groups. Shortly after, the receptor was named GPR30 according to its HGMW-approved symbol [6].

GPR30 was found to belong to the rhodopsin-like receptor superfamily and showed highest homology to the interleukin

The subcellular localization of GPR30

Controversies regarding GPR30 already start with the subcellular localization of the receptor. Using COS-7 cells transiently transfected with C-terminally GFP-tagged GPR30 and a specific antiserum directed against the C-terminus of GPR30, Revankar et al. demonstrated that GPR30 localized to the endoplasmic reticulum and not to the plasma membrane [9]. There was also no evidence for plasma membrane localization in carcinoma cells endogenously expressing GPR30, such as MCF-7 cells, SKBR3, JEG and

Towards the potential in vivo role of GPR30

During the last two decades, gene targeting in mice became a powerful tool to study the biological role of genes. Using this technique it has to be taken into account that the phenotype of a knockout mouse is not always exclusively due to the inactivation of the gene of interest. Several other factors, such as the targeting strategy, the genetic background, the breeding strategy, and environmental components can severely influence the observed phenotype [32]. Before analysing the phenotype of

Concluding remarks

Despite considerable efforts to deorphanize and analyze the function of GPR30 numerous uncertainties remain to be resolved. Multiple studies suggest a role for GPR30 in membrane-initiated estrogen signalling. Nevertheless, existing in vitro data do not unequivocally support the hypothesis that GPR30 directly acts as a G-protein-coupled estrogen receptor. As suggested earlier, GPR30 may act partly together with classical estrogen receptors as a collaborator in signalling cascades [45]. GPR30 may

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A critical review of fundamental controversies in the field of GPR30 research

Abstract

Section snippets

Discovery of GPR30

The subcellular localization of GPR30

Towards the potential in vivo role of GPR30

Concluding remarks

Biochem Biophys Res Commun

FEBS Lett

Genomics

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Genomics

J Biol Chem

J Biol Chem

Biochem Biophys Res Commun

Neurosci Lett

Progestin upregulates G-protein-coupled receptor 30 in breast cancer cells

Eur J Biochem

G protein-coupled receptor 30 is critical for a progestin-induced growth inhibition in MCF-7 breast cancer cells

Endocrinology

A transmembrane intracellular estrogen receptor mediates rapid cell signalling

Science

Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells

Endocrinology

Estrogen-induced activation of Erk-1 and Erk-2 requires the G-protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF

Mol Endocrinol

Alcohol and membrane-associated signal transduction

Alcohol Alcohol.

Estrogenic GPR30 signalling induces proliferation and migration of breast cancer cells through CTGF

EMBO J

Tamoxifen pharmacogenomics: the role of CYP2D6 as a predictor of drug response

Clin Pharmacol Ther

Effect of tamoxifen on carbachol-triggered intracellular calcium responses in chicken granulosa cells

Cancer Res

G Protein-coupled receptor 30 localizes to the endoplasmic reticulum and is not activated by estradiol

Endocrinology

Unexpected effects of epitope and chimeric tags on gonadotropin-releasing hormone receptors: implications for understanding the molecular etiology of hypogonadotropic hypogonadism

J Clin Endocrinol Metab

Regulatory role of G protein-coupled estrogen receptor for vascular function and obesity

Circ Res