HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bai, M. Articles by Brown, E. M. Search for Related Content PubMed PubMed Citation Articles by Bai, M. Articles by Brown, E. M. Social Bookmarking                      What's this?

J Biol Chem, Vol. 273, Issue 33, 21267-21275, August 14, 1998

Protein Kinase C Phosphorylation of Threonine at Position 888 in Ca²⁺_o-Sensing Receptor (CaR) Inhibits Coupling to Ca²⁺ Store Release

Mei Bai, Sunita Trivedi, Charles R. Lane, Yinhai Yang^¶, Steven J. Quinn, and Edward M. Brown

From the  Endocrine-Hypertension Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School and the ^¶ Department of Cardiology, Research Laboratory, Children's Hospital, Boston, Massachusetts 02115

Previous studies in parathyroid cells, which express the G protein-coupled, extracellular calcium-sensing receptor (CaR), showed that activation of protein kinase C (PKC) blunts high extracellular calcium (Ca²⁺_o)-evoked stimulation of phospholipase C and the associated increases in cytosolic calcium (Ca²⁺_i), suggesting that PKC may directly modulate the coupling of the CaR to intracellular signaling systems. In this study, we examined the role of PKC in regulating the coupling of the CaR to Ca²⁺_i dynamics in fura-2-loaded human embryonic kidney cells (HEK293 cells) transiently transfected with the human parathyroid CaR. We demonstrate that several PKC activators exert inhibitory effects on CaR-mediated increases in Ca²⁺_i due to release of Ca²⁺ from intracellular stores. Consistent with the effect being mediated by activation of PKC, the inhibitory effect of PKC activators on Ca²⁺ release can be blocked by a PKC inhibitor. The use of site-directed mutagenesis reveals that threonine at amino acid position 888 is the major PKC site that mediates the inhibitory effect of PKC activators on Ca²⁺ mobilization. The effect of PKC activation can be maximally blocked by mutating three PKC sites (Thr⁸⁸⁸, Ser⁸⁹⁵, and Ser⁹¹⁵) or all five PKC sites. In vitro phosphorylation shows that Thr⁸⁸⁸ is readily phosphorylated by PKC. Our results suggest that phosphorylation of the CaR is the molecular basis for the previously described effect of PKC activation on Ca²⁺_o-evoked changes in Ca²⁺_i dynamics in parathyroid cells.

---

Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				S. Smajilovic and J. Tfelt-Hansen Calcium acts as a first messenger through the calcium-sensing receptor in the cardiovascular system Cardiovasc Res, August 1, 2007; 75(3): 457 - 467. [Abstract] [Full Text] [PDF]

				S. L. Davies, A. Ozawa, W. D. McCormick, M. M. Dvorak, and D. T. Ward Protein Kinase C-mediated Phosphorylation of the Calcium-sensing Receptor Is Stimulated by Receptor Activation and Attenuated by Calyculin-sensitive Phosphatase Activity J. Biol. Chem., May 18, 2007; 282(20): 15048 - 15056. [Abstract] [Full Text] [PDF]

				S. Lorenz, R. Frenzel, R. Paschke, G. E. Breitwieser, and S. U. Miedlich Functional Desensitization of the Extracellular Calcium-Sensing Receptor Is Regulated via Distinct Mechanisms: Role of G Protein-Coupled Receptor Kinases, Protein Kinase C and {beta}-Arrestins Endocrinology, May 1, 2007; 148(5): 2398 - 2404. [Abstract] [Full Text] [PDF]

				E. M. Awumey, A. C. Howlett, J. W. Putney Jr., D. I. Diz, and R. D. Bukoski Ca2+ mobilization through dorsal root ganglion Ca2+-sensing receptor stably expressed in HEK293 cells Am J Physiol Cell Physiol, May 1, 2007; 292(5): C1895 - C1905. [Abstract] [Full Text] [PDF]

				A. D. Conigrave and E. M. Brown Taste Receptors in the Gastrointestinal Tract II. L-Amino acid sensing by calcium-sensing receptors: implications for GI physiology. Am J Physiol Gastrointest Liver Physiol, November 1, 2006; 291(5): G753 - G761. [Abstract] [Full Text] [PDF]

				S. L. Davies, C. E. Gibbons, T. Vizard, and D. T. Ward Ca2+-sensing receptor induces Rho kinase-mediated actin stress fiber assembly and altered cell morphology, but not in response to aromatic amino acids Am J Physiol Cell Physiol, June 1, 2006; 290(6): C1543 - C1551. [Abstract] [Full Text] [PDF]

				N. Chattopadhyay Effects of calcium-sensing receptor on the secretion of parathyroid hormone-related peptide and its impact on humoral hypercalcemia of malignancy Am J Physiol Endocrinol Metab, May 1, 2006; 290(5): E761 - E770. [Abstract] [Full Text] [PDF]

				J. Ohanian, K. M. Gatfield, D. T. Ward, and V. Ohanian Evidence for a functional calcium-sensing receptor that modulates myogenic tone in rat subcutaneous small arteries Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1756 - H1762. [Abstract] [Full Text] [PDF]

				M. Zhang and G. E. Breitwieser High Affinity Interaction with Filamin A Protects against Calcium-sensing Receptor Degradation J. Biol. Chem., March 25, 2005; 280(12): 11140 - 11146. [Abstract] [Full Text] [PDF]

				A. M. Sakwe, L. Rask, and E. Gylfe Protein Kinase C Modulates Agonist-sensitive Release of Ca2+ from Internal Stores in HEK293 Cells Overexpressing the Calcium Sensing Receptor J. Biol. Chem., February 11, 2005; 280(6): 4436 - 4441. [Abstract] [Full Text] [PDF]

				U. Peters, N. Chatterjee, M. Yeager, S. J. Chanock, R. E. Schoen, K. A. McGlynn, T. R. Church, J. L. Weissfeld, A. Schatzkin, and R. B. Hayes Association of Genetic Variants in the Calcium-Sensing Receptor with Risk of Colorectal Adenoma Cancer Epidemiol. Biomarkers Prev., December 1, 2004; 13(12): 2181 - 2186. [Abstract] [Full Text] [PDF]

				R. A. Chen and W. G. Goodman Role of the calcium-sensing receptor in parathyroid gland physiology Am J Physiol Renal Physiol, June 1, 2004; 286(6): F1005 - F1011. [Abstract] [Full Text] [PDF]

				A. De Luisi and A. M. Hofer Evidence that Ca2+ cycling by the plasma membrane Ca2+-ATPase increases the `excitability' of the extracellular Ca2+-sensing receptor J. Cell Sci., April 15, 2003; 116(8): 1527 - 1538. [Abstract] [Full Text] [PDF]

				Y.-F. Jiang, Z. Zhang, O. Kifor, C. R. Lane, S. J. Quinn, and M. Bai Protein Kinase C (PKC) Phosphorylation of the Ca2+o-sensing Receptor (CaR) Modulates Functional Interaction of G Proteins with the CaR Cytoplasmic Tail J. Biol. Chem., December 20, 2002; 277(52): 50543 - 50549. [Abstract] [Full Text] [PDF]

				S. H. Young, S. V. Wu, and E. Rozengurt Ca2+-stimulated Ca2+ Oscillations Produced by the Ca2+-sensing Receptor Require Negative Feedback by Protein Kinase C J. Biol. Chem., November 27, 2002; 277(49): 46871 - 46876. [Abstract] [Full Text] [PDF]

				S. X. Cheng, M. Okuda, A. E. Hall, J. P. Geibel, and S. C. Hebert Expression of calcium-sensing receptor in rat colonic epithelium: evidence for modulation of fluid secretion Am J Physiol Gastrointest Liver Physiol, July 1, 2002; 283(1): G240 - G250. [Abstract] [Full Text] [PDF]

				D. T. Ward, S. J. McLarnon, and D. Riccardi Aminoglycosides Increase Intracellular Calcium Levels and ERK Activity in Proximal Tubular OK Cells Expressing the Extracellular Calcium-Sensing Receptor J. Am. Soc. Nephrol., June 1, 2002; 13(6): 1481 - 1489. [Abstract] [Full Text] [PDF]

				G. E. Breitwieser and L. Gama Calcium-sensing receptor activation induces intracellular calcium oscillations Am J Physiol Cell Physiol, June 1, 2001; 280(6): C1412 - C1421. [Abstract] [Full Text] [PDF]

				B. D. Bennett, U. Alvarez, and K. A. Hruska Receptor-Operated Osteoclast Calcium Sensing Endocrinology, May 1, 2001; 142(5): 1968 - 1974. [Abstract] [Full Text]

				E. M. Brown and R. J. MacLeod Extracellular Calcium Sensing and Extracellular Calcium Signaling Physiol Rev, January 1, 2001; 81(1): 239 - 297. [Abstract] [Full Text] [PDF]

				S. U. Goebel, P. L. Peghini, P. K. Goldsmith, A. M. Spiegel, F. Gibril, M. Raffeld, R. T. Jensen, and J. Serrano Expression of the Calcium-Sensing Receptor in Gastrinomas J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4131 - 4137. [Abstract] [Full Text]

				A. Lienhardt, M. Garabédian, M. Bai, C. Sinding, Z. Zhang, J.-P. Lagarde, J. Boulesteix, M. Rigaud, E. M. Brown, and M.-L. Kottler A Large Homozygous or Heterozygous In-Frame Deletion within the Calcium-Sensing Receptor's Carboxylterminal Cytoplasmic Tail That Causes Autosomal Dominant Hypocalcemia J. Clin. Endocrinol. Metab., April 1, 2000; 85(4): 1695 - 1702. [Abstract] [Full Text]

				M. J. Rutten, K. D. Bacon, K. L. Marlink, M. Stoney, C. L. Meichsner, F. P. Lee, S. A. Hobson, K. D. Rodland, B. C. Sheppard, D. D. Trunkey, et al. Identification of a functional Ca2+-sensing receptor in normal human gastric mucous epithelial cells Am J Physiol Gastrointest Liver Physiol, September 1, 1999; 277(3): G662 - G670. [Abstract] [Full Text] [PDF]

				H. Awata, C. Huang, M. E. Handlogten, and R. T. Miller Interaction of the Calcium-sensing Receptor and Filamin, a Potential Scaffolding Protein J. Biol. Chem., September 7, 2001; 276(37): 34871 - 34879. [Abstract] [Full Text] [PDF]

				S. H. Young and E. Rozengurt Amino acids and Ca2+ stimulate different patterns of Ca2+ oscillations through the Ca2+-sensing receptor Am J Physiol Cell Physiol, June 1, 2002; 282(6): C1414 - C1422. [Abstract] [Full Text] [PDF]