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Updated: May 21, 2026

Modeling Paracrine Noncanonical Wnt Signaling In Vitro
Published on: December 10, 2021
Non-canonical signaling of the PTH receptor
Jean-Pierre Vilardaga1, Thomas J Gardella, Vanessa L Wehbi
1Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261, USA. jpv@pitt.edu
Abstract:
The classical model of arrestin-mediated desensitization of cell-surface G-protein-coupled receptors (GPCRs) is thought to be universal. However, this paradigm is incompatible with recent reports that the parathyroid hormone (PTH) receptor (PTHR), a crucial GPCR for bone and mineral ion metabolism, sustains G(S) activity and continues to generate cAMP for prolonged periods after ligand washout; during these periods the receptor is observed mainly in endosomes, associated with the bound ligand, G(S) and β-arrestins. In this review we discuss possible molecular mechanisms underlying sustained signaling by the PTHR, including modes of signal generation and attenuation within endosomes, as well as the biological relevance of such non-canonical signaling.
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