Megalin antagonizes activation of the parathyroid hormone receptor
- PMID: 10026179
- DOI: 10.1074/jbc.274.9.5620
Megalin antagonizes activation of the parathyroid hormone receptor
Abstract
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 (Kd 0.5 microM). 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.
Similar articles
-
Renal expression of parathyroid hormone-related protein (PTHrP) and PTH/PTHrP receptor in a rat model of tubulointerstitial damage.Kidney Int. 1999 Jan;55(1):82-90. doi: 10.1046/j.1523-1755.1999.00241.x. Kidney Int. 1999. PMID: 9893116
-
The extracellular amino-terminal region of the parathyroid hormone (PTH)/PTH-related peptide receptor determines the binding affinity for carboxyl-terminal fragments of PTH-(1-34).Endocrinology. 1994 Feb;134(2):879-84. doi: 10.1210/endo.134.2.8299582. Endocrinology. 1994. PMID: 8299582
-
Photoaffinity cross-linking identifies differences in the interactions of an agonist and an antagonist with the parathyroid hormone/parathyroid hormone-related protein receptor.J Biol Chem. 2000 Jan 7;275(1):9-17. doi: 10.1074/jbc.275.1.9. J Biol Chem. 2000. PMID: 10617579
-
Molecular mechanisms of ligand recognition by parathyroid hormone 1 (PTH1) and PTH2 receptors.Curr Pharm Des. 2001 May;7(8):689-713. doi: 10.2174/1381612013397825. Curr Pharm Des. 2001. PMID: 11375776 Review.
-
Parathyroid hormone-related peptide (PTHrP) and parathyroid hormone (PTH)/PTHrP receptor.Crit Rev Eukaryot Gene Expr. 1998;8(3-4):297-320. doi: 10.1615/critreveukargeneexpr.v8.i3-4.40. Crit Rev Eukaryot Gene Expr. 1998. PMID: 9807698 Review.
Cited by
-
Akt recruits Dab2 to albumin endocytosis in the proximal tubule.Am J Physiol Renal Physiol. 2014 Dec 15;307(12):F1380-9. doi: 10.1152/ajprenal.00454.2014. Epub 2014 Sep 24. Am J Physiol Renal Physiol. 2014. PMID: 25253241 Free PMC article.
-
Impaired PTH-induced endocytotic down-regulation of the renal type IIa Na+/Pi-cotransporter in RAP-deficient mice with reduced megalin expression.Pflugers Arch. 2003 Jul;446(4):475-84. doi: 10.1007/s00424-003-1057-4. Epub 2003 May 13. Pflugers Arch. 2003. PMID: 12748857
-
Physiological roles of CLC Cl(-)/H (+) exchangers in renal proximal tubules.Pflugers Arch. 2009 May;458(1):23-37. doi: 10.1007/s00424-008-0597-z. Epub 2008 Oct 14. Pflugers Arch. 2009. PMID: 18853181 Review.
-
Backbone Modification of a Parathyroid Hormone Receptor-1 Antagonist/Inverse Agonist.ACS Chem Biol. 2016 Oct 21;11(10):2752-2762. doi: 10.1021/acschembio.6b00404. Epub 2016 Aug 17. ACS Chem Biol. 2016. PMID: 27533344 Free PMC article.
-
Fluorescent ligand-directed co-localization of the parathyroid hormone 1 receptor with the brush-border scaffold complex of the proximal tubule reveals hormone-dependent changes in ezrin immunoreactivity consistent with inactivation.Biochim Biophys Acta. 2012 Dec;1823(12):2243-53. doi: 10.1016/j.bbamcr.2012.09.010. Epub 2012 Oct 2. Biochim Biophys Acta. 2012. PMID: 23036889 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Research Materials
Miscellaneous
