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Physiological activation of PKC-alpha via the calcium sensing receptor is not required for the Ca2+-regulated secretion of parathyroid hormone in dispersed bovine parathyroid cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
(English)Manuscript (Other academic)
Identifiers
URN: urn:nbn:se:uu:diva-92303OAI: oai:DiVA.org:uu-92303DiVA: diva2:165328
Available from: 2004-11-01 Created: 2004-11-01 Last updated: 2011-06-30Bibliographically approved
In thesis
1. The Role of Protein Kinase C in the Extracellular Ca2+-regulated Secretion of Parathyroid Hormone
Open this publication in new window or tab >>The Role of Protein Kinase C in the Extracellular Ca2+-regulated Secretion of Parathyroid Hormone
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Parathyroid hormone (PTH) is the major physiological regulator of the extracellular Ca2+ concentration ([Ca2+]o) in the body. The secretion of this hormone is suppressed at high [Ca2+]o. Previously this was thought to occur by intracellular degradation of the hormone in the secretory pathway of parathyroid (PT) cells but is now believed to result from extracellular Ca2+ stimulus-secretion coupling via the calcium sensing receptor (CaR). In contrast to the stimulation of PTH secretion upon inhibition of mature PTH proteolysis, inhibition of PT proteasomes caused the accumulation of PTH precursors and inhibited secretion of PTH. This suggests that PT proteasomes play a quality control function in the maturation of PTH but they do not directly participate in the [Ca2+]o-regulated secretion of the hormone. Treatment of PT cells with 12-O-tetradecanyolphorbol-13-acetate (TPA) blocks the high [Ca2+]o-induced CaR-mediated suppression of PTH secretion. To delineate the role of DAG-responsive protein kinase C (PKC) isoforms in this process, we complemented pharmacological modulation of PKC activity with physiological activation of the enzyme via the CaR. PKC-α was rapidly activated by high [Ca2+]o and was efficiently down-regulated by prolonged TPA treatment. In CaR-transfected HEK293 cells, TPA and high [Ca2+]o induced the activation of ERK1/2 but the TPA effect was CaR- and Ca2+-independent. The magnitude of neomycin-induced release of Ca2+ from intracellular stores following pharmacological modulation of PKC activity was opposite to that resulting from physiological activation/inhibition of the enzyme via the CaR. Influx of Ca2+ following activation of the receptor occurred by store-operated mechanisms. Over-expression of wt or DN PKC-α or-ε in PT cells using the Tet-On adenovirus gene delivery system revealed that the stimulatory effect of TPA on PTH secretion at high [Ca2+]o was enhanced in cells over-expressing wt PKC-α, but the coupling of the extracellular Ca2+ signal to PTH secretion was not dependent on the physiological activation of this PKC isoform via the CaR.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 47 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1384
Keyword
Medical sciences, parathyroid hormone, Ca2+, protein kinase C, calcium sensing receptor, ERK1/2, biosynthesis, secretion, MEDICIN OCH VÅRD
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-4637 (URN)91-554-6073-9 (ISBN)
Public defence
2004-11-26, C10:301, Uppsala Biomedical Center, Uppsala, 13:15
Opponent
Supervisors
Available from: 2004-11-01 Created: 2004-11-01Bibliographically approved

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Akusjärvi, Göran

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