Calcium-sensing receptor endocytosis links extracellular calcium signaling to parathyroid hormone-related peptide secretion via a Rab11a-dependent and AMSH-sensitive mechanism.
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.
Reyes-Ibarra
Alma P
AP
Centro de Investigación y de Estudios Avanzados-Instituto Politécnico Nacional, Cell Biology Department, México DF, México.
García-Regalado
Alejandro
A
Ramírez-Rangel
Iliana
I
Esparza-Silva
Ana L
AL
Valadez-Sánchez
Margarita
M
Vázquez-Prado
José
J
Reyes-Cruz
Guadalupe
G
D002118:Calcium / Q000494:pharmacology; D020013:Calcium Signaling; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D004705:Endocytosis; D056827:Endosomal Sorting Complexes Required for Transport; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism*; D044169:Receptors, Calcium-Sensing / Q000819:agonists / Q000032:analysis / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000099193:rab11 GTP-Binding Proteins
D002118:Calcium; D056827:Endosomal Sorting Complexes Required for Transport; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D044162:Parathyroid Hormone-Related Protein; D044169:Receptors, Calcium-Sensing; D043222:Ubiquitin Thiolesterase; D033921:Vesicular Transport Proteins; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C463459:GPRASP1 protein, human; C486696:STAMBP protein, human