Does GPER Really Function as a G Protein-Coupled Estrogen Receptor in vivo?

Abstract

Estrogen can elicit pleiotropic cellular responses via a diversity of estrogen receptors (ERs)-mediated genomic and rapid non-genomic mechanisms. Unlike the genomic responses, where the classical nuclear ERα and ERβ act as transcriptional factors following estrogen binding to regulate gene transcription in estrogen target tissues, the non-genomic cellular responses to estrogen are believed to start at the plasma membrane, leading to rapid activation of second messengers-triggered cytoplasmic signal transduction cascades. The recently acknowledged ER, GPR30 or GPER, was discovered in human breast cancer cells two decades ago and subsequently in many other cells. Since its discovery, it has been claimed that estrogen, ER antagonist fulvestrant, as well as some estrogenic compounds can directly bind to GPER, and therefore initiate the non-genomic cellular responses. Various recently developed genetic tools as well as chemical ligands greatly facilitated research aimed at determining the physiological roles of GPER in different tissues. However, there is still lack of evidence that GPER plays a significant role in mediating endogenous estrogen action in vivo. This review summarizes current knowledge about GPER, including its tissue expression and cellular localization, with emphasis on the research findings elucidating its role in health and disease. Understanding the role of GPER in estrogen signaling will provide opportunities for the development of new therapeutic strategies to strengthen the benefits of estrogen while limiting the potential side effects.

Effects and Mechanisms of Phthalates’ Action on Reproductive Processes and Reproductive Health: A Literature Review

“…GPER together with ER regulate Leydig cell function in males [ 36 ]. However, GPER is associated with reproductive tissue cancer, such as breast, ovary, endometrium, testis or prostate [ 37 ]. The membrane progesterone receptor regulates oocyte maturation, labor, and sperm motility and reproductive organs cancer onset [ 35 ].…”

Continuous Exposure of Breast Cancer Cells to Tamoxifen Upregulates GPER-1 and Increases Cell Proliferation

“…In general, breast cancer is classified as estrogen receptor alpha (ERα) positive or negative. ERα-positive tumors comprise approximately 70% of all breast tumors and depend on estrogen to develop and grow ( 1 , 2 ). It has been estimated that a large number of the responses mediated by 17β-estradiol, a kind of estrogen, occur through its binding to ERα, triggering a “genomic response” that initiates the transcription of genes associated to cell proliferation, survival and migration ( 1 , 3 ).…”

“…G protein-coupled estrogen receptor-1 (GPER-1 or GPR30) is a G protein-coupled receptor (GPCR) sited in the cell membrane that triggers a broad range of biological activities in response to stimulation by endogenous estrogens or dietary phytoestrogens ( 2 , 7 ). Its gene is located on chromosome 7p22.3 and encodes a protein of 375 amino acids with a theoretical molecular mass of 41 kDa that is ubiquitously expressed in a large number of tissues ( 8 – 11 ).…”

Differential ESR1 Promoter Methylation in the Peripheral Blood—Findings from the Women 40+ Healthy Aging Study

“…Indeed, ERα contributes to maintain biological functions such as cardiovascular, metabolic, cognitive, hypothalamic, and limbic functions, even under conditions of low estrogen levels [27,28]. This might be due to the higher affinity of ERα with E2, compared to the affinity with E2 of the other ER subtypes [29,30]. Moreover, studies on osteoporosis indicate that ERα, but not ERβ, is essential in promoting bone-protective actions and bone formation [18,31].…”

“…Furthermore, a decrease in the relative expression of ERα/ERβ, mainly due to a loss of ERα, is associated with cognitive impairments and a loss of E2 responsiveness in advanced age [27,29]. Concerning GPER, its role as a plasma membrane-based ER is controversial, and there is still a lack of evidence that this ER plays a significant role in mediating endogenous estrogen effects in vivo [30].…”