ArticleProceedings of the National Academy of Sciences of the United States of America1999
Phosphorylation-independent inhibition of parathyroid hormone receptor signaling by G protein-coupled receptor kinases.
Article in Proceedings of the National Academy of Sciences of the United States of America, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 137 citations in OpenAlex.
- Deciphering the role of glycosaminoglycans in GPCR signaling.Cellular signalling · 2024Review
- The Intricacies of Renal Phosphate Reabsorption-An Overview.International journal of molecular sciences · 2024Review
- Therapeutic antagonism of the neurokinin 1 receptor in endosomes provides sustained pain relief.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Molecular Mechanisms of PTH/PTHrP Class B GPCR Signaling and Pharmacological Implications.Endocrine reviews · 2023Article
- Functional modulation of PTH1R activation and signaling by RAMP2.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- GPCR kinase knockout cells reveal the impact of individual GRKs on arrestin binding and GPCR regulation.Nature communications · 2022Article
- Site-specific polyubiquitination differentially regulates parathyroid hormone receptor-initiated MAPK signaling and cell proliferation.The Journal of biological chemistry · 2018Article
- Identification of key phosphorylation sites in PTH1R that determine arrestin3 binding and fine-tune receptor signaling.The Biochemical journal · 2016Article
- GRK2 Constitutively Governs Peripheral Delta Opioid Receptor Activity.Cell reports · 2016Article
- Regulation of Fc∈RI signaling in mast cells by G protein-coupled receptor kinase 2 and its RH domain.The Journal of biological chemistry · 2014Article
- Time-resolved fluorescence ligand binding for G protein-coupled receptors.Nature protocols · 2013Article
- Regulation of Constitutive GPR3 Signaling and Surface Localization by GRK2 and β-arrestin-2 Overexpression in HEK293 Cells.PloS one · 2013Article
- Roles of phosphorylation-dependent and -independent mechanisms in the regulation of histamine H2 receptor by G protein-coupled receptor kinase 2.The Journal of biological chemistry · 2011Article
- Regulation of the epithelial Na+ channel by the RH domain of G protein-coupled receptor kinase, GRK2, and Galphaq/11.The Journal of biological chemistry · 2011Article
- The physiological roles of phosducin: from retinal function to stress-dependent hypertension.Cellular and molecular life sciences : CMLS · 2011Review
- Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm.Cellular and molecular life sciences : CMLS · 2011Review
- Formation of a ternary complex among NHERF1, beta-arrestin, and parathyroid hormone receptor.The Journal of biological chemistry · 2010Article
- Regulation of Lrp6 phosphorylation.Cellular and molecular life sciences : CMLS · 2010Review
- The TIP39-PTH2 receptor system: unique peptidergic cell groups in the brainstem and their interactions with central regulatory mechanisms.Progress in neurobiology · 2010Review
- G Protein-coupled receptor kinases phosphorylate LRP6 in the Wnt pathway.The Journal of biological chemistry · 2009Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Homologous desensitization of G protein-coupled receptors is thought to occur in several steps: binding of G protein-coupled receptor kinases (GRKs) to receptors, receptor phosphorylation, kinase dissociation, and finally binding of beta-arrestins to phosphorylated receptors. It generally is assumed that only the last step inhibits receptor signaling. Investigating the parathyroid hormone (PTH) receptor --> inositol phosphate pathway, we report here that GRKs can inhibit receptor signaling already under nonphosphorylating conditions. GRKs phosphorylated the PTH receptor in membranes and in intact cells; the order of efficacy was GRK2>GRK3>GRK5. Transient transfection of GRKs with the PTH receptor into COS-1 cells inhibited PTH-stimulated inositol phosphate generation. Such an inhibition also was seen with the kinase-negative mutant GRK2-K220R and also for a C-terminal truncation mutant of the PTH receptor that could not be phosphorylated. Several lines of evidence indicated that this phosphorylation-independent inhibition was exerted by an interaction between GRKs and receptors: (a) this inhibition was not mimicked by proteins binding to G proteins, phosducin, and GRK2 C terminus, (b) GRKs caused an agonist-dependent inhibition (= desensitization) of receptor-stimulated G protein GTPase-activity (this effect also was seen with the kinase-inactive GRK2-mutant and the phosphorylation-deficient receptor mutant), and (c) GRKs bound directly to the PTH receptor. These data suggest that signaling by the PTH receptor already is inhibited by the first step of homologous desensitization, the binding of GRKs to the receptors.
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