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      G Protein-Coupled Receptors: Extranuclear Mediators for the Non-Genomic Actions of Steroids

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          Abstract

          Steroids hormones possess two distinct actions, a delayed genomic effect and a rapid non-genomic effect. Rapid steroid-triggered signaling is mediated by specific receptors localized most often to the plasma membrane. The nature of these receptors is of great interest and accumulated data suggest that G protein-coupled receptors (GPCRs) are appealing candidates. Increasing evidence regarding the interaction between steroids and specific membrane proteins, as well as the involvement of G protein and corresponding downstream signaling, have led to identification of physiologically relevant GPCRs as steroid extranuclear receptors. Examples include G protein-coupled receptor 30 (GPR30) for estrogen, membrane progestin receptor for progesterone, G protein-coupled receptor family C group 6 member A (GPRC6A) and zinc transporter member 9 (ZIP9) for androgen, and trace amine associated receptor 1 (TAAR1) for thyroid hormone. These receptor-mediated biological effects have been extended to reproductive development, cardiovascular function, neuroendocrinology and cancer pathophysiology. However, although great progress have been achieved, there are still important questions that need to be answered, including the identities of GPCRs responsible for the remaining steroids (e.g., glucocorticoid), the structural basis of steroids and GPCRs’ interaction and the integration of extranuclear and nuclear signaling to the final physiological function. Here, we reviewed the several significant developments in this field and highlighted a hypothesis that attempts to explain the general interaction between steroids and GPCRs.

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          Most cited references 77

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          A transmembrane intracellular estrogen receptor mediates rapid cell signaling.

          The steroid hormone estrogen regulates many functionally unrelated processes in numerous tissues. Although it is traditionally thought to control transcriptional activation through the classical nuclear estrogen receptors, it also initiates many rapid nongenomic signaling events. We found that of all G protein-coupled receptors characterized to date, GPR30 is uniquely localized to the endoplasmic reticulum, where it specifically binds estrogen and fluorescent estrogen derivatives. Activating GPR30 by estrogen resulted in intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus. Thus, GPR30 represents an intracellular transmembrane estrogen receptor that may contribute to normal estrogen physiology as well as pathophysiology.
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            Estrogen receptors: how do they signal and what are their targets.

            During the past decade there has been a substantial advance in our understanding of estrogen signaling both from a clinical as well as a preclinical perspective. Estrogen signaling is a balance between two opposing forces in the form of two distinct receptors (ER alpha and ER beta) and their splice variants. The prospect that these two pathways can be selectively stimulated or inhibited with subtype-selective drugs constitutes new and promising therapeutic opportunities in clinical areas as diverse as hormone replacement, autoimmune diseases, prostate and breast cancer, and depression. Molecular biological, biochemical, and structural studies have generated information which is invaluable for the development of more selective and effective ER ligands. We have also become aware that ERs do not function by themselves but require a number of coregulatory proteins whose cell-specific expression explains some of the distinct cellular actions of estrogen. Estrogen is an important morphogen, and many of its proliferative effects on the epithelial compartment of glands are mediated by growth factors secreted from the stromal compartment. Thus understanding the cross-talk between growth factor and estrogen signaling is essential for understanding both normal and malignant growth. In this review we focus on several of the interesting recent discoveries concerning estrogen receptors, on estrogen as a morphogen, and on the molecular mechanisms of anti-estrogen signaling.
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              Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells.

              Although nonclassical estrogen actions initiated at the cell surface have been described in many tissues, the identities of the membrane estrogen receptors (mERs) mediating these actions remain unclear. Here we show that GPR30, an orphan receptor unrelated to nuclear estrogen receptors, has all the binding and signaling characteristics of a mER. A high-affinity (dissociation constant 2.7 nm), limited capacity, displaceable, single binding site specific for estrogens was detected in plasma membranes of SKBR3 breast cancer cells that express GPR30 but lack nuclear estrogen receptors. Progesterone-induced increases and small interfering RNA-induced decreases in GPR30 expression in SKBR3 cells were accompanied by parallel changes in specific estradiol-17beta (E2) binding. Plasma membranes of human embryonic kidney 293 cells transfected with GPR30, but not those of untransfected cells, and human placental tissues that express GPR30 also displayed high-affinity, specific estrogen binding typical of mERs. E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity. The finding that the antiestrogens tamoxifen and ICI 182,780, and an environmental estrogen, ortho,para-dichlorodiphenyldichloroethylene (o,p'-DDE), have high binding affinities to the receptor and mimic the actions of E2 has important implications for both the development and treatment of estrogen-dependent breast cancer. GPR30 is structurally unrelated to the recently discovered family of GPCR-like membrane progestin receptors. The identification of a second distinct class of GPCR-like steroid membrane receptors suggests a widespread role for GPCRs in nonclassical steroid hormone actions.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                01 September 2014
                September 2014
                : 15
                : 9
                : 15412-15425
                Affiliations
                [1 ]Department of Medicine, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China; E-Mail: mcherry.f@ 123456gmail.com
                [2 ]Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China; E-Mail: liuyi.dream@ 123456gmail.com
                [3 ]Department of Physiology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: caojm@ 123456ibms.pumc.edu.cn ; Tel.: +86-10-6915-6959; Fax: +86-10-6915-6467.
                Article
                ijms-15-15412
                10.3390/ijms150915412
                4200746
                25257522
                © 2014 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                Categories
                Review

                Molecular biology

                non-genomic effect, g protein-coupled receptor, steroid

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