Elsevier

Steroids

Volume 81, March 2014, Pages 74-80
Steroids

Review
Role of ERα36 in membrane-associated signaling by estrogen

https://doi.org/10.1016/j.steroids.2013.10.020Get rights and content

Abstract

Traditionally, steroid hormones such as the vitamin D3 metabolites, testosterone and dihydrotesterone, and 17β-estradiol act through cytosolic and nuclear receptors that directly interact with DNA to alter gene transcription and regulate cellular development. However, recent studies focused on rapid and membrane effects of steroid hormones have given invaluable insight into their non-classical mechanisms of action. In some cases, the traditional receptors were implicated as acting also in the plasma membrane as membrane-associated receptors. However, recent data have demonstrated the presence of an alternative splicing variant to traditional estrogen receptor α known as ERα36, which is present in the plasma membranes of several different cell types including several cancer cell types and even in some normal cells including cartilage and bone cells. The physiological effects that result from the membrane activation of ERα36 may vary from one cell type to another, but the mechanism of action appears to use similar pathways such as the activation of various protein kinases and phospholipases leading to the activation of signaling cascades that result in rapid, non-genomic responses. These rapid responses can affect cell proliferation and apoptotic signaling, indirectly activate downstream genomic signaling through phosphorylation cascades of transcription factors, and crosstalk with classical pathways via interaction with classical receptors. This review describes the data from the last several years and discusses the non-classical, rapid, and membrane-associated cellular responses to steroid hormones, particularly 17β-estradiol, through the classical receptors ERα and ERβ and various non-classical receptors, especially estrogen receptor-α36 (ERα36).

Introduction

Estrogens regulate skeletal development and breast development in addition to regulating reproductive development [1]. These aforementioned functions are of particular interest as they are deleteriously affected by deficiency or abnormalities in estrogen signaling resulting in debilitating conditions, such as osteopenia or breast cancer progression [2], [3]. Estrogen normally regulates osteoblast and osteoclast function, thus abnormal estrogen levels following menopause may result in dysregulation of bone remodeling, leading to decreases in bone mineral retention, and ultimately causing osteopenia, a precursor to osteoporosis [4]. Causes of breast cancer are not as easily identified, but estrogen is a well-accepted as mediator of breast cancer progression. Moreover abnormal estrogen can promote progression of hormone-responsive cancers, such as uterine, ovarian, cervical and laryngeal [5], [6]. Therefore, the role of estrogen receptors in normal and abnormal physiological conditions is crucial to the understanding and treatment of these conditions.

Section snippets

Steroid hormones and non-classical receptor signaling pathways

Estrogens belong to the class of biomolecules known as steroid hormones, which traditionally confer their effects through direct interaction with hormone-specific nuclear receptors. These include vitamin D3 metabolites such as 1α,25-dihydroxyvitamin-D3 (1α,25(OH)2D3) with the nuclear vitamin D3 receptor (VDR or nVDR), androgens such as testosterone and dihydrotestosterone (DHT) with androgen receptors (ARs), and estrogens, particularly 17β-estradiol (E2), with the estrogen receptors (ERs), ERα

Sexual dimorphism and estrogen receptors

As expected, presence of ERs and response to estradiol exhibit sexual dimorphism. Many studies on estrogen function and estrogen receptors are performed using breast cancer cells, which are typically from female cancers, and sexual dimorphism is not at issue. However, studies in non-cancerous tissues such as bone and cartilage illustrate the sexual dimorphism in physiological response to E2 [32]. What is surprising is that male cells still contain all the necessary signaling equipment necessary

Pathway cross-talk

Fig. 7 illustrates the various mechanisms by which ERs can mediate intracellular signaling. There remains an uncertainty as to an exclusive role of ERα36 as a membrane-associated receptor for E2. Studies on its role in breast and laryngeal cancer show that it works independently of traditional ERα, ERβ, and GPR30 [6], [34], [38]. It is clear that it can promote rapid signaling from the caveolae and from lipid rafts in the plasma membrane. Data also show that in non-cancerous tissue such as

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