The Role of Protein Kinase C in the Extracellular Ca²⁺-regulated Secretion of Parathyroid Hormone

Description

<p>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.</p>

Links & Downloads

1. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4637
2. ISBN 91-554-6073-9

Tags

Medical sciences

parathyroid hormone

Ca2+

protein kinase C

calcium sensing receptor

ERK1/2

biosynthesis

secretion

MEDICIN OCH VÅRD

MEDICINE

MEDICIN

Additional Fields

Identifer	oai:union.ndltd.org:UPSALLA/oai:DiVA.org:uu-4637
Date	January 2004
Creators	Sakwe, Amos M.
Publisher	Uppsala University, Department of Medical Biochemistry and Microbiology, Uppsala : Acta Universitatis Upsaliensis
Source Sets	DiVA Archive at Upsalla University
Language	English
Detected Language	English
Type	Doctoral thesis, comprehensive summary, text
Relation	Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 0282-7476 ; 1384