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Calcium-sensing receptor stimulates PTHrP release by pathways dependent on PKC, p38 MAPK, JNK, and ERK1/2 in H-500 cells

¹Endocrine-Hypertension Division, Department of Medicine and Membrane Biology Program, Brigham and Women's Hospital and Harvard Medical School, and ²Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Institutes of Medicine, Boston, Massachusetts 02115; and ³Osteoporosis and Bone Metabolic Unit, Department of Clinical Biochemistry and Endocrinology, Copenhagen University Hospital, Hvidovre, DK-2650, Denmark

Submitted 11 November 2002 ; accepted in final form 11 April 2003

Elevated extracellular calcium ([Ca²⁺]_o) and other agonists potentially acting via the calcium-sensing receptor (CaR) increase parathyroid hormone-related peptide (PTHrP) release from H-500 Leydig cells. Here, we provide strong evidence for the CaR's involvement by using a dominant negative CaR that attenuates high [Ca²⁺]_o-induced PTHrP release. This effect is likely transcriptional, because high [Ca²⁺]_o upregulates the 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 the stress-activated protein kinase SEK1 is PKC independent, because 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.

G protein-coupled receptor; Leydig cells; humoral hypercalcemia of malignancy; dominant negative; stress-activated protein kinase activator 1; osteolysis

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