ArticleThe Journal of biological chemistry2011
Roles of phosphorylation-dependent and -independent mechanisms in the regulation of histamine H2 receptor by G protein-coupled receptor kinase 2.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 32 citations in OpenAlex.
- Recent advances in the development of GRK2 inhibitors: blocking the interaction of GRK2 with its partners.Acta pharmacologica Sinica · 2026Review
- Adrenoceptor Desensitization: Current Understanding of Mechanisms.Pharmacological reviews · 2024Review
- Function and Role of Histamine HPharmaceuticals (Basel, Switzerland) · 2023Review
- Novel inhibitors of phosphorylation independent activity of GRK2 modulate cAMP signaling.Pharmacology research & perspectives · 2022Article
- Suitability of GRK Antibodies for Individual Detection and Quantification of GRK Isoforms in Western Blots.International journal of molecular sciences · 2022Article
- Resolvin D2 and Resolvin D1 Differentially Activate Protein Kinases to Counter-Regulate Histamine-Induced [CaInternational journal of molecular sciences · 2021Article
- The Roles of Cardiovascular HFrontiers in pharmacology · 2021Review
- The Regulator of G Protein Signaling Homologous Domain of G Protein-Coupled Receptor Kinase 2 Mediates Short-Term Desensitization of β3-Adrenergic Receptor.Frontiers in pharmacology · 2020Article
- GRK2 promotes growth of medulloblastoma cells and protects them from chemotherapy-induced apoptosis.Scientific reports · 2019Article
- International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors.Pharmacological reviews · 2015Review
- Physiological implications of biased signaling at histamine H2 receptors.Frontiers in pharmacology · 2015Article
- Differential β₂-adrenergic receptor expression defines the phenotype of non-tumorigenic and malignant human breast cell lines.Oncotarget · 2014Article
- 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
- Cross-desensitization and cointernalization of H1 and H2 histamine receptors reveal new insights into histamine signal integration.Molecular pharmacology · 2013Article
- Regulation of Constitutive GPR3 Signaling and Surface Localization by GRK2 and β-arrestin-2 Overexpression in HEK293 Cells.PloS one · 2013Article
- Molecular and cellular analysis of human histamine receptor subtypes.Trends in pharmacological sciences · 2013Review
- GRK2 protein-mediated transphosphorylation contributes to loss of function of μ-opioid receptors induced by neuropeptide FF (NPFF2) receptors.The Journal of biological chemistry · 2012Article
- GRK2: multiple roles beyond G protein-coupled receptor desensitization.Trends in pharmacological sciences · 2012Review
- The secret life of kinases: functions beyond catalysis.Cell communication and signaling : CCS · 2011Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
It is widely assumed that G protein-coupled receptor kinase 2 (GRK2)-mediated specific inhibition of G protein-coupled receptors (GPCRs) response involves GRK-mediated receptor phosphorylation followed by β-arrestin binding and subsequent uncoupling from the heterotrimeric G protein. It has recently become evident that GRK2-mediated GPCRs regulation also involves phosphorylation-independent mechanisms. In the present study we investigated whether the histamine H2 receptor (H2R), a Gα(s)-coupled GPCR known to be desensitized by GRK2, needs to be phosphorylated for its desensitization and/or internalization and resensitization. For this purpose we evaluated the effect of the phosphorylating-deficient GRK2K220R mutant on H2R signaling in U937, COS7, and HEK293T cells. We found that although this mutant functioned as dominant negative concerning receptor internalization and resensitization, it desensitized H2R signaling in the same degree as the GRK2 wild type. To identify the domains responsible for the kinase-independent receptor desensitization, we co-transfected the receptor with constructions encoding the GRK2 RGS-homology domain (RH) and the RH or the kinase domain fused to the pleckstrin-homology domain. Results demonstrated that the RH domain of GRK2 was sufficient to desensitize the H2R. Moreover, disruption of RGS functions by the use of GRK2D110A/K220R double mutant, although coimmunoprecipitating with the H2R, reversed GRK2K220R-mediated H2R desensitization. Overall, these results indicate that GRK2 induces desensitization of H2R through a phosphorylation-independent and RGS-dependent mechanism and extends the GRK2 RH domain-mediated regulation of GPCRs beyond Gα(q)-coupled receptors. On the other hand, GRK2 kinase activity proved to be necessary for receptor internalization and the resulting resensitization.
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