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Am J Physiol Endocrinol Metab 284: E435-E442, 2003. First published October 8, 2002; doi:10.1152/ajpendo.00143.2002
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Vol. 284, Issue 2, E435-E442, February 2003

PTHrP stimulated by the calcium-sensing receptor requires MAP kinase activation

R. John MacLeod, Naibedya Chattopadhyay, and Edward M. Brown

Endocrine-Hypertension Division and Membrane Biology Program, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

Increases in extracellular calcium concentration ([Ca2+]o) stimulate from normal and malignant cells secretion of parathroid hormone-related protein (PTHrP), a major mediator of humoral hypercalcemia of malignancy. Because the calcium-sensing receptor (CaR) is a determinant of calcium-regulated hormone secretion, we examined whether HEK cells stably transfected with human CaR secreted PTHrP in response to CaR stimulation. Increases in [Ca2+]o or neomycin and Gd3+ all substantially increased PTHrP secretion in CaR-HEK cells but had no effect on nontransfected cells. CaR activation likewise increased PTHrP transcripts. PD-098059 and U-0126, inhibitors of the mitogen-activated protein kinase kinase MEK1/2, abolished CaR-stimulated secretion but had no effect on basal secretion. An inhibitor of p38 MAP kinase, SB-203580, also attenuated CaR-stimulated secretion. Western analysis revealed that CaR activation caused a robust increase in MEK1/2 and p38 MAP kinase phosphorylation. A Src family kinase inhibitor, PP2, blocked both basal and CaR-stimulated secretion. We conclude that CaR specifically mediates the effect of increasing [Ca2+]o on PTHrP synthesis and secretion and that activated MEK1/2 and p38 MAP kinases are determinants of the CaR's stimulation of PTHrP secretion.

parathroid hormone-related protein secretion; calcium-sensing receptor; mitogen-activated protein kinase; p38; mitogen-activated and extracellular signal-regulated protein kinase-1 and -2


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