Non-canonical signaling of the PTH receptor.
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.
Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261, USA. jpv@pitt.edu
Jean-Pierre
JP
Vilardaga
Thomas J
TJ
Gardella
Vanessa L
VL
Wehbi
Timothy N
TN
Feinstein
D000818:Animals; D019390:Arrestins / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D011487:Protein Conformation; D018016:Receptors, Parathyroid Hormone / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction; D000071557:beta-Arrestins
D019390:Arrestins; D018016:Receptors, Parathyroid Hormone; D000071557:beta-Arrestins; D000242:Cyclic AMP; D019204:GTP-Binding Proteins