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Title: Rapid effects of 17β-estradiol on hepatocytes
Author: Stratton, Rebecca Claire
ISNI:       0000 0004 2691 2040
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2008
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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.
Supervisor: Not available Sponsor: Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH301 Biology