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Submitted on January 30, 2002
Accepted on August 27, 2002
1 Endocrine Research Unit, VA Medical Center, University of California San Francisco, San Francisco CA 94121
* To whom correspondence should be addressed. E-mail: chicago{at}itsa.ucsf.edu.
The recovery of PTH receptor (PTHR) function after acute homologous receptor desensitization and down-regulation in bone and kidney cells has been attributed to receptor recycling. To determine the role of receptor dephosphorylation in PTHR recycling, we performed morphological and functional assays on HEK293 cells stably expressing wild-type or mutant PTHRs. Confocal microscopy and ligand binding assays revealed that the wild-type PTHR is rapidly recycled back to the plasma membrane after removal of the agonist. Receptors that were engineered to either lack the sites of phosphorylation or to resemble constitutively phosphorylated receptors were able to recycle back to the plasma membrane with the same kinetics as the wild-type PTHR. The PTHR was found to be dephosphorylated by an enzyme apparently distinct from protein phosphatases 1 or 2A. The PTHR and ß-arrestin-2-GFP were found to stably co-localize during PTHR internalization whereas after agonist removal and during receptor recycling, the co-localization slowly disappeared. Experiments using phosphorylation-deficient PTHRs and a dominant-negative form of ß-arrestin showed that ß-arrestin does not regulate the efficiency of PTHR recycling. These studies indicate that, unlike many GPCRs, PTHR recycling does not require receptor dephosphorylation or its dissociation from ß-arrestin.
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