Involvement of protein kinase C-alpha and -epsilon in extracellular Ca signalling mediated by the calcium sensing receptor |
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Authors: | Amos M Sakwe Mrten Larsson Lars Rask |
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Institution: | aDepartment of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden |
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Abstract: | The sensing of extracellular Ca2+ concentration (Ca2+]o) and modulation of cellular processes associated with acute or sustained changes in Ca2+]o are cell-type specific and mediated by the calcium sensing receptor (CaR). Ca2+]o signalling requires protein kinase C (PKC), but the identity and role of PKC isoforms in CaR-mediated responses remain unclear. Here we show that high Ca2+]o activated PKC-α and PKC-ε in parathyroid cells and in human embryonic kidney (HEK293) cells overexpressing the CaR (HEK-CaR) and that this response correlated with the CaR-dependent activation of mitogen-activated protein kinases ERK1/2. Activation of ERK1/2 by acute high Ca2+]o required influx of Ca2+through Ni2+-sensitive Ca2+channels and phosphatidylinositol-dependent phospholipase C-β activity. Inhibition of PKC by co-expression of dominant-negative (DN) mutants of PKC-α or -ε with the CaR attenuated sustained ERK1/2 activation. Overexpression of a PKC phosphorylation site (T888A) mutant CaR in HEK293 cells showed that this site was important for ERK1/2 activation at high Ca2+]o. Activation of ERK1/2 by high Ca2+]o was not necessary for the Ca2+]o-regulated secretion of parathyroid hormone (PTH) in dispersed bovine parathyroid cells. These data suggest that the CaR-mediated Ca2+]o signal leading to regulated PTH secretion that requires diacylglycerol-responsive PKC isoforms is not mediated via the ERK pathway. |
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Keywords: | Parathyroid cells PTH Calcium sensing receptor Protein kinase C ERK1/2 Calcium channels |
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