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) Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hilpert, J. Articles by Willnow, T. E. Search for Related Content PubMed PubMed Citation Articles by Hilpert, J. Articles by Willnow, T. E. Social Bookmarking                      What's this?

J Biol Chem, Vol. 274, Issue 9, 5620-5625, February 26, 1999

Megalin Antagonizes Activation of the Parathyroid Hormone Receptor

Jan Hilpert, Anders Nykjaer^§, Christian Jacobsen^¶, Gerd Wallukat^§, Rikke Nielsen, Soeren K. Moestrup^¶, Hermann Haller, Friedrich C. Luft, Erik I. Christensen, and Thomas E. Willnow^§

From the  Franz-Volhard-Clinic, Humboldt-University and ^§ Max-Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany, Departments of ^¶ Medical Biochemistry and  Cell Biology, University of Aarhus, 8000 Aarhus, Denmark

Parathyroid hormone (PTH) is predominantly cleared from the circulation by glomerular filtration and degradation in the renal proximal tubules. Here, we demonstrate that megalin, a multifunctional endocytic receptor in the proximal tubular epithelium, mediates the uptake and degradation of PTH. Megalin was purified from kidney membranes as the major PTH-binding protein and shown in BIAcore analysis to specifically bind full-length PTH and amino-terminal PTH fragments (K_d 0.5 µM). Absence of the receptor in megalin knockout mice resulted in 4-fold increased levels of amino-terminal PTH fragments in the urine. In F9 cells expressing both megalin and the PTH/PTH-related peptide receptor (PTH/PTHrP receptor), uptake and lysosomal degradation of the hormone was mediated through megalin. Blocking megalin-mediated clearance of PTH resulted in 3-fold increased stimulation of the PTH/PTHrP receptor. These data provide evidence that megalin is involved in the renal catabolism of PTH and potentially antagonizes PTH/PTHrP receptor activity in the proximal tubular epithelium.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				U. Anzenberger, N. Bit-Avragim, S. Rohr, F. Rudolph, B. Dehmel, T. E. Willnow, and S. Abdelilah-Seyfried Elucidation of megalin/LRP2-dependent endocytic transport processes in the larval zebrafish pronephros J. Cell Sci., May 15, 2006; 119(10): 2127 - 2137. [Abstract] [Full Text] [PDF]

				T. J. Jentsch Chloride Transport in the Kidney: Lessons from Human Disease and Knockout Mice J. Am. Soc. Nephrol., June 1, 2005; 16(6): 1549 - 1561. [Abstract] [Full Text] [PDF]

				T. M. Murray, L. G. Rao, P. Divieti, and F. R. Bringhurst Parathyroid Hormone Secretion and Action: Evidence for Discrete Receptors for the Carboxyl-Terminal Region and Related Biological Actions of Carboxyl- Terminal Ligands Endocr. Rev., February 1, 2005; 26(1): 78 - 113. [Abstract] [Full Text] [PDF]

				R. Spoelgen, A. Hammes, U. Anzenberger, D. Zechner, O. M. Andersen, B. Jerchow, and T. E. Willnow LRP2/megalin is required for patterning of the ventral telencephalon Development, January 15, 2005; 132(2): 405 - 414. [Abstract] [Full Text] [PDF]

				P. R. Cutillas, R. J. Chalkley, K. C. Hansen, R. Cramer, A. G. W. Norden, M. D. Waterfield, A. L. Burlingame, and R. J. Unwin The urinary proteome in Fanconi syndrome implies specificity in the reabsorption of proteins by renal proximal tubule cells Am J Physiol Renal Physiol, September 1, 2004; 287(3): F353 - F364. [Abstract] [Full Text] [PDF]

				H. Hama, A. Saito, T. Takeda, A. Tanuma, Y. Xie, K. Sato, J. J. Kazama, and F. Gejyo Evidence Indicating that Renal Tubular Metabolism of Leptin Is Mediated by Megalin But Not by the Leptin Receptors Endocrinology, August 1, 2004; 145(8): 3935 - 3940. [Abstract] [Full Text] [PDF]

				S. Bachmann, U. Schlichting, B. Geist, K. Mutig, T. Petsch, D. Bacic, C. A. Wagner, B. Kaissling, J. Biber, H. Murer, et al. Kidney-Specific Inactivation of the Megalin Gene Impairs Trafficking of Renal Inorganic Sodium Phosphate Cotransporter (NaPi-IIa) J. Am. Soc. Nephrol., April 1, 2004; 15(4): 892 - 900. [Abstract] [Full Text] [PDF]

				F. R. Bringhurst Circulating Forms of Parathyroid Hormone: Peeling Back the Onion Clin. Chem., December 1, 2003; 49(12): 1973 - 1975. [Full Text] [PDF]

				A. Saito, J. J. Kazama, N. Iino, K. Cho, N. Sato, H. Yamazaki, Y. Oyama, T. Takeda, R. A. Orlando, F. Shimizu, et al. Bioengineered Implantation of Megalin-Expressing Cells: A Potential Intracorporeal Therapeutic Model for Uremic Toxin Protein Clearance in Renal Failure J. Am. Soc. Nephrol., August 1, 2003; 14(8): 2025 - 2032. [Abstract] [Full Text] [PDF]

				A. Saito, R. Nagai, A. Tanuma, H. Hama, K. Cho, T. Takeda, Y. Yoshida, T. Toda, F. Shimizu, S. Horiuchi, et al. Role of Megalin in Endocytosis of Advanced Glycation End Products: Implications for a Novel Protein Binding to Both Megalin and Advanced Glycation End Products J. Am. Soc. Nephrol., May 1, 2003; 14(5): 1123 - 1131. [Abstract] [Full Text] [PDF]

				O. Devuyst and W. B. Guggino Chloride channels in the kidney: lessons learned from knockout animals Am J Physiol Renal Physiol, December 1, 2002; 283(6): F1176 - F1191. [Abstract] [Full Text] [PDF]

				W. G. Goodman, I. B. Salusky, and H. Juppner New lessons from old assays: parathyroid hormone (PTH), its receptors, and the potential biological relevance of PTH fragments Nephrol. Dial. Transplant., October 1, 2002; 17(10): 1731 - 1736. [Full Text] [PDF]

				T. J. Jentsch, V. Stein, F. Weinreich, and A. A. Zdebik Molecular Structure and Physiological Function of Chloride Channels Physiol Rev, April 1, 2002; 82(2): 503 - 568. [Abstract] [Full Text] [PDF]

				E. I. Christensen and H. Birn Megalin and cubilin: synergistic endocytic receptors in renal proximal tubule Am J Physiol Renal Physiol, April 1, 2001; 280(4): F562 - F573. [Abstract] [Full Text] [PDF]

				E. Feraille and A. Doucet Sodium-Potassium-Adenosinetriphosphatase-Dependent Sodium Transport in the Kidney: Hormonal Control Physiol Rev, January 1, 2001; 81(1): 345 - 418. [Abstract] [Full Text] [PDF]

				M. Marino, G. Zheng, L. Chiovato, A. Pinchera, D. Brown, D. Andrews, and R. T. McCluskey Role of Megalin (gp330) in Transcytosis of Thyroglobulin by Thyroid Cells. A NOVEL FUNCTION IN THE CONTROL OF THYROID HORMONE RELEASE J. Biol. Chem., March 15, 2000; 275(10): 7125 - 7137. [Abstract] [Full Text] [PDF]

				E. I. CHRISTENSEN and T. E. WILLNOW Essential Role of Megalin in Renal Proximal Tubule for Vitamin Homeostasis J. Am. Soc. Nephrol., October 1, 1999; 10(10): 2224 - 2236. [Full Text]

				W Hampe, J Urny, I Franke, S. Hoffmeister-Ullerich, D Herrmann, C. Petersen, J Lohmann, and H. Schaller A head-activator binding protein is present in hydra in a soluble and a membrane-anchored form Development, January 9, 1999; 126(18): 4077 - 4086. [Abstract] [PDF]