Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm.
The parathyroid hormone (PTH) receptor type 1 (PTHR), a G protein-coupled receptor (GPCR), transmits signals to two hormone systems-PTH, endocrine and homeostatic, and PTH-related peptide (PTHrP), paracrine-to regulate different biological processes. PTHR responds to these hormonal stimuli by activating heterotrimeric G proteins, such as G(S) that stimulates cAMP production. It was thought that the PTHR, as for all other GPCRs, is only active and signals through G proteins on the cell membrane, and internalizes into a cell to be desensitized and eventually degraded or recycled. Recent studies with cultured cell and animal models reveal a new pathway that involves sustained cAMP signaling from intracellular domains. Not only do these studies challenge the paradigm that cAMP production triggered by activated GPCRs originates exclusively at the cell membrane but they also advance a comprehensive model to account for the functional differences between PTH and PTHrP acting through the same receptor.
Vilardaga
Jean-Pierre
JP
Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA. jpv@pitt.edu
Romero
Guillermo
G
Friedman
Peter A
PA
Gardella
Thomas J
TJ
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D010281:Parathyroid Hormone / Q000737:chemistry / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism; D017434:Protein Structure, Tertiary; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013329:Structure-Activity Relationship
D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D044168:Receptor, Parathyroid Hormone, Type 1; D000242:Cyclic AMP; D019204:GTP-Binding Proteins