The ins and outs of GPR30: A transmembrane estrogen receptor

Abstract

Estrogen is an important hormone in human physiology. It acts both via transcriptional regulation as well as via modulation of intracellular signaling through second messengers. Although estrogen's transcriptional effects occur through classical nuclear steroid receptors (ERs), recent studies reveal the existence of a novel 7-transmembrane G protein-coupled receptor, GPR30, which responds to estrogen and tamoxifen stimulation with rapid cellular signaling including ERK activation, PI3K activation, calcium mobilization and cAMP production. To distinguish between ER- and GPR30-mediated signaling, we have identified a novel GPR30 agonist that exhibits high specificity for GPR30. In this review, we will describe recent work to further our understanding of the role of GPR30 in estrogen biology.

Introduction

Estrogen (E2) is a critical hormone in the human body, regulating functionally dissimilar processes in numerous tissues. Estrogen is one member of the family of steroid hormones, which also includes progesterone, testosterone, cortisol/glucocorticoids and aldosterone/mineralocorticoids that control many aspects of mammalian physiology. Steroid hormones are synthesized in tissues throughout the body, including the ovaries (estrogen, progesterone), testes (androgens/testosterone) and adrenal glands (cortisol, androgens and aldosterone). Additional estrogen-based steroids, estrone and estriol are also known to mediate biological functions. Among estrogen's diverse physiological effects are the regulation of growth, development and homeostasis of numerous tissues. The best understood of these are mammalian female reproduction and breast development [1]. In addition, estrogen regulates skeletal physiology [2], (cardio)vascular function [3] and the central nervous system [4] as well as the immune system [5]. Estrogen modulates processes ranging from adhesion and migration to survival and proliferation, cardiovascular and neuro-protection, organogenesis, angiogenesis and cancer. In addition, neurological processes such as stress responses, feeding patterns, sleep cycles and temperature regulation have been shown to be modulated by estrogen [6], [7]. In the clinical arena, estrogen is perhaps most appreciated for its role in stimulating the proliferation of approximately two thirds of breast cancers [8], [9].

Estrogen-like activity can also be found in a large variety of sources, both natural and man-made. These include phytoestrogens/isoflavonoids, from plants and fungi [10], as well as xenoestrogens, which include a variety of pesticides, polychlorinated biphenyls and plasticizers [11], [12]. Diethylstilbestrol (DES), for example, was used from 1938-1971 as a treatment for pregnant women who experienced miscarriages or premature deliveries [13]. In utero, exposure to DES has been shown to have carcinogenic, teratogenic and reproductive effects on both the original patient as well as the children of treated individuals [14]. The majority of such compounds are thought to exert their effects through the inappropriate activation of estrogen receptor(s) [15].

The physiological effects of estrogens are traditionally mediated by nuclear hormone estrogen receptors (originally termed ER but later ERα), first characterized in the 1960's and 1970's, [16]. A second estrogen receptor, ERβ, discovered in 1996 [17], complicated our understanding of estrogen action. ERβ is highly homologous to ERα and the two receptors are clearly evolutionarily related. The recent cloning of a mollusk estrogen receptor homolog that fails to bind estrogen suggests that the steroid receptors may be much more ancient than previously thought [18], [19]. Steroid receptors, including ERα and ERβ, display a modular organization consisting of a ligand-binding domain, a DNA-binding domain and two transcriptional activation function domains. Binding of estrogen to ERs results in the release of the receptor from an inhibitory complex with heat shock proteins, allowing the receptor monomer to dimerize, translocate to the nucleus and associate with co-activating transcriptional factors. The DNA- and ligand-binding domains of ERα and ERβ are 97% and 60% homologous, respectively. However, the amino terminus, which contains one of the transcriptional activation domains is only 18% homologous between the two ER subtypes [20]. Thus, both receptors bind estrogen and estrogen analogs with similar, though not identical, affinities/specificities and recognize identical DNA sequences. Distinct patterns of tissue distribution and the characterization of ERα and ERβ knockout mice, however, reveal many differences in function [21].