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Dissertation
Molecular membrane interactions of cortisol and 17[beta]-estradiol: implications for a membrane lipid-mediated mechanism of steroid hormone action
Doctor of Philosophy (Ph.D.), Allegheny University of the Health Sciences
Mar 1998
DOI:
https://doi.org/10.17918/00007371
Abstract
There is strong evidence to support the hypothesis that many rapid cellular effects of steroids are membrane-mediated, including the demonstration of rapid steroid actions in the absence of intracellular receptors, in the presence of RNA or protein synthesis inhibitors, and in response to steroids coupled to large proteins that prevent intracellular access. However, the basic mechanisms responsible for mediating the membrane effects of steroids are not well understood. This dissertation examines the basic biochemical and physical interactions of steroid hormones with biomembranes to gain new insight into the mechanism(s) involved in rapid steroid actions. It has been hypothesized that steroid hormones, like cholesterol, intercalate into the membrane bilayer and indirectly modulate integral membrane protein activity by perturbing certain physical characteristics of the lipid matrix. This hypothesis was tested by selecting two naturally occurring steroids, a glucocorticoid (cortisol) and a sex steroid (17[beta]-estradiol), and using them to (1) measure steroid partitioning into model cell membranes, (2) determine the effect of membrane-composition on steroid partititioning, (3) identify the energetically-favorable membrane binding locations of steroids and their effects on membrane structure, and (4) measure rapid steroid effects on a human integral membrane protein (Na?, K?-ATPase). At physiological conditions, these steroids intercalated rapidly to distinct regions of the membrane bilayer and exhibited high membrane-based paritition coefficients. In the membrane, these steroids altered important biophysical and functional properties, as assessed by small angle x-ray diffraction and ion flux measurements. These data suggest that steroid-membrane interactions are highly sensitive to both hormonal stereochemistry and membrane lipid composition, and that rapid steroid effects may occur in the absence of direct steroid-protein interactions; thereby contributing to our understanding of the rapid cellular effects of steroid hormones.
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Details
- Title
- Molecular membrane interactions of cortisol and 17[beta]-estradiol
- Creators
- Gil Adam Golden
- Contributors
- R. Preston Mason (Advisor) - Drexel University, Allegheny University of the Health Sciences (1996-1998)Robert T. Rubin (Advisor) - Drexel University, Allegheny University of the Health Sciences (1996-1998)
- Awarding Institution
- Allegheny University of the Health Sciences
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Allegheny University of the Health Sciences; Philadelphia, Pennsylvania
- Number of pages
- xii, 85 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Allegheny University of the Health Sciences (1996-1998); School of Medicine (1996-1998)
- Other Identifier
- 991021888757604721