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Title: The role of protein kinase C in anterior pituitary hormone release
Author: Thomson, Fiona J.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1993
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The role of protein kinase C (PKC) in luteinizing hormone-releasing hormone (LHRH)-induced luteinizing hormone (LH) release and in the priming effect of LHRH (the unique ability of LHRH to increase pituitary responsiveness to itself) was examined. Using pro-oestrous rat anterior pituitary pieces, incubated in vitro, the PKC inhibitors, staurosporine, Ro 31-8220 and 1-(5-isoquinolinesulphonyl)-2-methylpiperazine (H7) inhibited the induction of LHRH priming, but had no effect on initial, unprimed LHRH-induced release of LH. Although the primed response was readily inhibited by staurosporine and Ro 31-8220, it was unusually resistant to block by H7, suggesting that the induction of LHRH priming may involve activation of an H7-resistant form of PKC or PKC-like kinase. Since the PKC(s) which control LH release may have a distinct pharmacological profile, the effect of PKC inhibitors and activators (phorbol 12,13-dibutyrate (PDBu) 1,2-dioctanoyl-sn-glycerol (DOG) and mezerein) on hormone release was examined in more detail. Mezerein and PDBu both induced LH and growth hormone (GH) release, whereas LH, but not GH, release could be induced by DOG. Thus DOG may activate at least some of the PKC forms which induce LH release, but not those which induce GH release. Although PKC activator-induced LH and GH release were readily inhibited by staurosporine, PDBu- and mezerein-induced GH release were resistant to block by H7. Furthermore PKC activator-induced LH release displayed both H7-sensitive and H7-resistant components. Cytosolic PKC activity, partially purified from anterior pituitary, was measured in a mixed micelle assay. A PDBu-induced, Ca2+-independent, histone kinase activity was detected which was relatively resistant to H7. In contrast, Ca2+-dependent PKC activity displayed the expected sensitivity to H7. Therefore, the H7-resistant PKCs which have a role in LHRH-priming, LH release and GH release may be of the Ca2+-independent type. Further attempts to characterise the H7-resistant kinase(s) by H7 displacement of [3H]-dimethylstaurosporine binding on sites in different tissues were made, but only limited conclusions could be drawn since the binding sites on PKC for these two inhibitors appear to be non-identical.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available