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1 Department of Medicine and Membrane Biology Program, Endocrine-Hypertension Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
2 Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Institutes of Medicine, Boston, MA, USA
3 Department of Clinical Biochemistry and Endocrinology, Osteoporosis and Bone Metabolic Unit, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
* To whom correspondence should be addressed. E-mail: jtfelt{at}rics.bwh.harvard.edu.
Elevated extracellular calcium (Ca2+o) and other agonists potentially acting via the calcium-sensing receptor (CaR) increase PTHrP release from H-500 leydig cells. Here, we provide strong evidence for the CaR's involvement using a dominant negative CaR that attenuates high Ca2+o-induced PTHrP release. This effect is likely transcriptional as high Ca2+o upregulates PTHrP transcript, an effect that is abolished by actinomycin D. Regulation of PTHrP release by the CaR involves activation of PKC as well as ERK1/2, p38 MAPK and JNK pathways. However, we show for the first time that high Ca2+o-induced activation of SEK1 is PKC independent as there is an additive effect of a PKC inhibitor in combination with the JNK inhibitor on Ca2+o-stimulated PTHrP release. Furthermore, high Ca2+o, in a PKC independent fashion, induces phosphorylation of ERK1/2, SEK1, p38 MAPK and its downstream transcription factor ATF-2. We conclude that CaR regulation of PTHrP release in H-500 cells involves activation of PKC as well as the ERK1/2, p38 MAPK and JNK pathways.
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