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Articles in PresS, published online ahead of print October 8, 2002
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00143.2002
Submitted on April 2, 2002
Accepted on October 1, 2002
1 Endocrine-Hypertension Division and Membrane Biology Program, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: rmacleod{at}rics.bwh.harvard.edu.
Increases in extracellular calcium (Ca2+o) concentration 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 non-transfected cells. CaR activation likewise increased PTHrP transcripts. PD098059 and U0126, 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, SB203580, 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 activation of MEK1&2 and p38 MAPKs are determinants of the CaR's stimulation of PTHrP secretion.
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