Caveolae Linked to Nongenomic Actions and Uptake of Estrogen

The initial paradigm of sex hormone action in the cell begins with the delivery of sex hormones to the cell surface, passage across the plasma membrane, interaction with a receptor localized in the cytosol, and transport of the hormone-receptor complex to the nucleus, where the sex hormone-bound receptor acts to alter specific gene transcription. During the early 1990s, a few studies showed that the initial model proposing that the steroid receptor was the cytosolic chaperone for these hydrophobic compounds (which do not diffuse readily through an aqueous environment) was in fact incorrect, since the majority of the estrogen receptors were found exclusively in the nucleus. The initial studies which observed estrogen receptors within the cytosol were due to an artifact that occurred during processing [51,52]. In the absence of ligand, the receptor had a lowered binding affinity for DNA, causing the receptor to leak out of the nucleus. Thus, the initial steps that were posited to explain uptake and transportation across the cytosol to the nucleus no longer had a mechanistic explanation. Additionally, to date, there is still no mechanism in place to account for the initial uptake of sex hormone by cells, or to explain how sex hormones cross the plasma membrane to enter the cell, or what regulates delivery to the nucleus or sites of nongenomic action. A number of recent studies have begun to fill in this gap, however. The first point to be made was that caveolae mark cholesterol-rich membranes which are organized into a network in the cell, providing an organized set of membranes through which other sterols can "diffuse". The second point was the discovery that the estrogen receptor is found associated with caveolae at the plasma membrane [53-55]. The third point is the recent finding that activation of nitric oxide by sex hormones requires a specific pool of estrogen which is tightly associated with HDL [14]. Estrogen is tightly bound specifically with HDL, and HDL from female mice - but not male mice - activates eNOS. The activation of eNOS is linked to HDL binding to SR-BI and SR-BI-mediated delivery of estrogen to caveolae. This study was the first to identify caveolae as a putative site of uptake of estrogen into endothelial cells. The results of these studies, taken together, define an emerging new paradigm of sex hormone delivery to cells and transport of sex hormones from the plasma membrane to specific intracellular organelles which initiate in caveolae. The role of intracellular caveolin-associated membranes in estrogen trafficking within the cell remains to be elucidated. This emerging paradigm of the first steps in estrogen delivery to cells may represent a new paradigm for the uptake of some other sterols. Recently, vitamin D was shown to bind to a pool of the nuclear vitamin D receptor, which localizes to caveolae in the intestine [56,57]. Thus, the initial inter action of vitamin D with cells and many of its nongenomic actions appears to extend this emerging model of sex hormone uptake to a model that may be important in a broader context of other sterols. In addition, it might also provide novel insights into the uptake and action of other lipophilic hormones, vitamins, and nutrients.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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