Role of ERα36 in membrane-associated signaling by estrogen

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).