Rapid effects of 17β-estradiol on hepatocytes
Stratton, Rebecca Claire (2008) Rapid effects of 17β-estradiol on hepatocytes. PhD thesis, University of Warwick.Full text not available from this repository.
Official URL: http://webcat.warwick.ac.uk/record=b2334550~S15
17β-estradiol is the most potent circulating estrogenic hormone. The classical mode of action of 17β-estradiol involves its translocation to the nucleus and regulation of transcription. However, numerous rapid, non-genomic actions of 17β-estradiol have been demonstrated in several cell types. This thesis demonstrates that 17β-estradiol rapidly elevates hepatocyte cGMP and stimulates plasma membrane Ca2+ efflux. In contrast, 17α-estradiol, an optical isomer, is without effect on cGMP or Ca2+ efflux. The Ca2+ efflux stimulation is protein kinase G (PKG)-dependent. This thesis also demonstrates the expression of PKG isoforms Iα and Iβ in hepatocytes, and that 17β-estradiol rapidly recruits PKGIα to the hepatocyte plasma membrane.
The observed effects of 17β-estradiol are mimicked by 17β-estradiol rendered membrane-impermeant by linkage to BSA. Moreover, 17β-estradiol binding at the hepatocyte plasma membrane was directly visualised using fluoroscein-labelled 17β-estradiol-BSA. The nature of the plasma membrane receptor involved was found to have a similar pharmacological profile to the ‘γ-adrenergic receptor’.
17β-estradiol protects both liver and isolated hepatocytes under pathophysiological conditions that have been associated with a rise in intracellular Ca2+ concentration ([Ca2+]i). Hepatoprotection by 17β-estradiol has previously been attributed to its antioxidant properties. A rise in [Ca2+]i is a common early event in cell injury, activating many Ca2+-dependent enzymes including calpain. Single cell Ca2+ measurements showed that 17β-estradiol attenuates both the amplitude and duration of ATP-induced [Ca2+]i rises. 17β-estradiol protects hepatocytes against the [Ca2+]i-dependent elevation of calpain activity and the decline in cell viability induced by both ATP and the bile acid taurolithocholate. The effects of 17β-estradiol on [Ca2+]i, calpain activity and cell viability are dependent on PKG. I propose that 17β-estradiol stimulates plasma membrane Ca2+ efflux through elevation of cGMP and subsequent activation and recruitment of PKGIα to the plasma membrane; this is a potential mechanism through which 17β-estradiol protects hepatocytes by alleviating harmful [Ca2+]i rises.
|Item Type:||Thesis or Dissertation (PhD)|
|Subjects:||Q Science > QH Natural history > QH301 Biology|
|Library of Congress Subject Headings (LCSH):||Liver cells -- Research, Estradiol, Transcription factors -- Research|
|Official Date:||September 2008|
|Institution:||University of Warwick|
|Theses Department:||Department of Biological Sciences|
|Supervisor(s)/Advisor:||Green, Anne K.|
|Sponsors:||Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC)|
|Extent:||1 v. (various pagings) : ill., charts|
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