ArticleProceedings of the National Academy of Sciences of the United States of America2013
Noncanonical GPCR signaling arising from a PTH receptor-arrestin-Gβγ complex.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 98 papers.
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Who cites it
98 citing papers in PubMed, 180 citations in OpenAlex.
- Spatial control of parathyroid hormone receptor-1 signaling dictates ligand-specific biological outcomes.Signal transduction and targeted therapy · 2026Article
- Inhibitory probes for spatiotemporal analysis of GαNature chemical biology · 2026Article
- Arrestins as programmable integrators of GPCR signaling: structural microstates, spatiotemporal logic, and therapeutic control.Cell discovery · 2026Review
- The working lives of neuronal 5-HTRSC chemical biology · 2026Review
- Mechanisms limiting the long-term anabolic effects of teriparatide (PTH 1-34) on bone.JBMR plus · 2026Review
- Regulation of cAMP levels in osteocytes by mechano-sensitive focal adhesion kinase and phosphodiesterase 8A.iScience · 2026Article
- Nf2 orchestrates β-arrestin2-biased PTH1R signaling to couple bone mass with skeletal integrity.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Altered Intracellular Trafficking as a Mechanism for Prolonged Duration of G Protein-Coupled Receptor Activation.Journal of the American Chemical Society · 2026Article
- Cooperative Control of Arrestin Activation By Membrane Lipids And Phosphorylation Barcodes.bioRxiv : the preprint server for biology · 2026Article
- Re-evaluating Gα protein-response element specificity in GPCR signaling.Communications biology · 2026Article
- Structure-Encoded Location Biased Signaling in a Class B GPCR: Focus on the PTH Type 1 Receptor.Handbook of experimental pharmacology · 2026Review
- Class A and B GPCRs trigger rapid GαCommunications biology · 2025Article
- Opioid receptors reveal a discrete cellular mechanism of endosomal G protein activation.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Intersection of GPCR trafficking and cAMP signaling at endomembranes.The Journal of cell biology · 2025Review
- Endosomal chemokine receptor signalosomes regulate central mechanisms underlying cell migration.eLife · 2025Article
- The Molecular Biology of Placental Transport of Calcium to the Human Foetus.International journal of molecular sciences · 2025Review
- Fast-diffusing receptor collisions with slow-diffusing peptide ligand assemble the ternary parathyroid hormone-GPCR-arrestin complex.Nature communications · 2024Article
- Article
- Role of the V2R-βarrestin-Gβγ complex in promoting G protein translocation to endosomes.Communications biology · 2024Article
- Beneath the surface: endosomal GPCR signaling.Trends in biochemical sciences · 2024Review
38 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
G protein-coupled receptors (GPCRs) participate in ubiquitous transmembrane signal transduction processes by activating heterotrimeric G proteins. In the current "canonical" model of GPCR signaling, arrestins terminate receptor signaling by impairing receptor-G-protein coupling and promoting receptor internalization. However, parathyroid hormone receptor type 1 (PTHR), an essential GPCR involved in bone and mineral metabolism, does not follow this conventional desensitization paradigm. β-Arrestins prolong G protein (G(S))-mediated cAMP generation triggered by PTH, a process that correlates with the persistence of arrestin-PTHR complexes on endosomes and which is thought to be associated with prolonged physiological calcemic and phosphate responses. This presents an inescapable paradox for the current model of arrestin-mediated receptor-G-protein decoupling. Here we show that PTHR forms a ternary complex that includes arrestin and the Gβγ dimer in response to PTH stimulation, which in turn causes an accelerated rate of G(S) activation and increases the steady-state levels of activated G(S), leading to prolonged generation of cAMP. This work provides the mechanistic basis for an alternative model of GPCR signaling in which arrestins contribute to sustaining the effect of an agonist hormone on the receptor.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.