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Calcium-Sensing Receptor Endocytosis Links Extracellular Calcium Signaling to Parathyroid Hormone-Related Peptide Secretion via a Rab11a-Dependent and AMSH-Sensitive Mechanism

Departments of Cell Biology (A.P.R.-I., A.G.-R., M.V.-S., G.R.-C.) and Pharmacology (I.R.-R., A.L.E.-S., J.V.-P.), Centro de Investigación y de Estudios Avanzados-Instituto Politécnico Nacional, 07000 México D.F., México

Address all correspondence and requests for reprints to: Guadalupe Reyes-Cruz, Ph.D., Centro de Investigación y de Estudios Avanzados-Instituto Politécnico Nacional, Cell Biology Department, Avenida Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360 México D.F., México. E-mail: guadaluper{at}cell.cinvestav.mx.

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.