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J. Biol. Chem., Vol. 283, Issue 36, 24435-24447, September 5, 2008

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Switching of G-protein Usage by the Calcium-sensing Receptor Reverses Its Effect on Parathyroid Hormone-related Protein Secretion in Normal Versus Malignant Breast Cells^*

Ramanaiah Mamillapalli, Joshua VanHouten, Walter Zawalich, and John Wysolmerski¹

From the Section of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine and School of Nursing, Yale University, New Haven, Connecticut 06520

The calcium-sensing receptor (CaR) is a G-protein-coupled receptor that signals in response to extracellular calcium and regulates parathyroid hormone secretion. The CaR is also expressed on normal mammary epithelial cells (MMECs), where it has been shown to inhibit secretion of parathyroid hormone-related protein (PTHrP) and participate in the regulation of calcium and bone metabolism during lactation. In contrast to normal breast cells, the CaR has been reported to stimulate PTHrP production by breast cancer cells. In this study, we confirmed that the CaR inhibits PTHrP production by MMECs but stimulates PTHrP production by Comma-D cells (immortalized murine mammary cells) and MCF-7 human breast cancer cells. We found that changes in intracellular cAMP, but not phospholipase C or MAPK signaling, correlated with the opposing effects of the CaR on PTHrP production. Pharmacologic stimulation of cAMP accumulation increased PTHrP production by normal and transformed breast cells. Inhibition of protein kinase A activity mimicked the effects of CaR activation on inhibiting PTHrP secretion by MMECs and blocked the effects of the CaR on stimulating PTHrP production in Comma-D and MCF-7 cells. We found that the CaR coupled to G_i in MMECs but coupled to G_s in Comma-D and MCF-7 cells. Thus, the opposing effects of the CaR on PTHrP production are because of alternate G-protein coupling of the receptor in normal versus transformed breast cells. Because PTHrP contributes to hypercalcemia and bone metastases, switching of G-protein usage by the CaR may contribute to the pathogenesis of breast cancer.

Received for publication, March 4, 2008 , and in revised form, May 26, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants DK077565, DK69542, and DK41230 from the NIDDK. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Section of Endocrinology and Metabolism, Dept. of Internal Medicine, Yale School of Medicine, P. O. Box 208020, New Haven, CT 06520-8020. Tel.: 203-785-7447; Fax: 203-785-6015; E-mail: john.wysolmerski{at}yale.edu.

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