Calcium-sensing receptor endocytosis links extracellular calcium signaling to parathyroid hormone-related peptide secretion via a Rab11a-dependent and AMSH-sensitive mechanism

Mol Endocrinol. 2007 Jun;21(6):1394-407. doi: 10.1210/me.2006-0523. Epub 2007 Apr 10.


The calcium-sensing receptor (CaR) helps to maintain the homeostasis of extracellular calcium by controlling the secretion of hormones associated with this process. The mechanism of agonist-induced endocytosis and down-regulation of CaR and the influence of this event on the secretion of CaR-regulated hormones is not fully understood. In this study, we show that CaR is constitutively endocytosed and recycled to the plasma membrane by a Rab11a-dependent mechanism; during this process, the level of total cellular CaR is maintained. This trafficking of CaR promotes the secretion of PTH-related peptide (PTHrP), as evidenced by a decrease on PTHrP secretion in the presence of a dominant-negative mutant of Rab11a. Interestingly, this Rab11a dominant-negative mutant does not interfere with CaR-dependent activation of ERK 1/2, suggesting that ERK signaling is not sufficient to promote PTHrP secretion downstream of CaR. In addition, AMSH (associated molecule with the SH3 domain of STAM), a CaR carboxyl-terminal binding protein, redirects CaR from slow recycling to down-regulation, reducing CaR expression and decreasing PTHrP secretion. Our results indicate that endocytosis and trafficking of CaR modulate PTHrP secretion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / pharmacology
  • Calcium Signaling*
  • Cell Membrane / chemistry
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Endocytosis*
  • Endosomal Sorting Complexes Required for Transport
  • Humans
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Parathyroid Hormone-Related Protein / metabolism*
  • Receptors, Calcium-Sensing / agonists
  • Receptors, Calcium-Sensing / analysis
  • Receptors, Calcium-Sensing / metabolism*
  • Ubiquitin Thiolesterase / metabolism*
  • Vesicular Transport Proteins / metabolism
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism*


  • Endosomal Sorting Complexes Required for Transport
  • GPRASP1 protein, human
  • Parathyroid Hormone-Related Protein
  • Receptors, Calcium-Sensing
  • STAMBP protein, human
  • Vesicular Transport Proteins
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Ubiquitin Thiolesterase
  • rab11 protein
  • rab GTP-Binding Proteins
  • Calcium