Extranuclear estrogen receptor's roles in physiology: lessons from mouse models

Abstract

Levin ER. Extranuclear estrogen receptor's roles in physiology: lessons from mouse models. Am J Physiol Endocrinol Metab 307: E133-E140, 2014. First published June 3, 2014 doi:10.1152/ajpendo.00626.2013.-Steroid receptors exist and function in multiple compartments of cells in most organs. Although the functions and nature of some of these receptors is being defined, important aspects of receptor localization and signaling to physiology and pathophysiology have been identified. In particular, extranuclear sex steroid receptors have been found in many normal cells and in epithelial tumors, where they enact signal transduction that impacts both nongenomic and genomic functions. Here, I focus on the progress made in understanding the roles of extranuclear estrogen receptors (ER) in physiology and pathophysiology. Extranuclear ER serve as a model to selectively intervene with novel receptor reagents to prevent or limit disease progression. Recent novel mouse models and membrane ER-selective agonists also provide a better understanding of receptor pool cross-talk that results in the overall integrative actions of sex steroids. membrane estrogen receptor; signal transduction; steroid receptors MORE THAN HALF A CENTURY AGO, the eminent endocrinologist Hans Selye first described rapid actions of steroid hormones in mammals (58). Rapid actions of glucocorticoids in vascular models were not consistent with the emerging field of gene regulation by nuclear steroid receptors. Because of technological limitations, the mediators of these rapid actions of glucocorticoids were not defined in that period. In contrast, in the 1960s and 1970s, Pietras and Szego (48,49), along with Szego and Davis (59), described rapid actions of estrogen, including calcium flux and cAMP generation that occurred in seconds after exposure of cells to this steroid. These authors provided evidence of estrogen binding to a presumed receptor, possibly at the cell surface, but the nature of this probable binding protein was unknown. These observations were consistent with the later description and isolation of a membrane protein that served as a receptor for plant brassinosteroids, bona fide steroids that mediate flowering and fertility. The brassinosteroid receptor was found to be a plasma membrane tyrosine kinase (64), establishing that the ancient and conserved function of steroids from plants to humans results from actions at the membrane. These rapid signals seemed unlikely to emanate from nuclear receptors, whose transcriptional function was defined as being much slower.Today, we know that the distribution of steroid receptors in vertebrates favors nuclear localization. Increased genome complexity occurs as one moves up the phylogenetic order and probably provides the impetus for evolution to create nuclear pools of steroid receptors. This allows binding of these receptors to promoters and especially multiple steroid response elements at enhancer DNA throughout the genome of many cells, regulating gene expression that is necessary for normal develo...

Retinoic acid regulates Kit translation during spermatogonial differentiation in the mouse

“…However, relatively modest changes in the transcriptome after RA exposure (Shima et al 2004; Zhou et al 2008a) suggests other avenues of RA-based regulation may be utilized in the neonatal testis. It has become clear that there are also non-genomic consequences of signaling downstream of RA (reviewed in (Al Tanoury et al 2013)), as with other hormone-receptor interactions, examples of which involve signaling through the estrogen receptor (ER) (Levin 2014), androgen receptor (AR) (Walker 2003), and glucocorticoid receptor (GR) (Revollo and Cidlowski 2009). RAR alpha (RARA) was shown in several cell types (SH-SY5Y, NIH3T3, and MEFs) to be bound to the regulatory subunit (p85) of PI3K; addition of RA recruited the catalytic subunit (p110) to induce rapid phosphorylation of ERK and AKT (Lopez-Carballo et al 2002; Masia et al 2007).…”

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Perimenopause as a neurological transition state

“…63 In the specialized caveolar involutions of the intracellular side of the plasma membrane, membranebound ERα and ERβ (mERα and mERβ) are associated with activation of fastacting signalling pathways, such as the PI3K-Akt and MAPK cascades. 48,64 Activation of fastacting signalling cascades is one of several mechanisms by which estrogen regu lates gene transcription ( Figure 3). In the case of estrogen receptor activation of the PI3K-Akt and MAPK path ways, estrogen binding to its receptor initiates a signalling cascade that leads to the phosphorylation and activation of CREB transcription factors, which upregulate expres sion of genes encoding proteins involved in learning and memory, synaptic transmission and neural growth factors such as brainderived neurotrophic factor.…”