ArticleThe Journal of biological chemistry2008
Cholesterol-dependent separation of the beta2-adrenergic receptor from its partners determines signaling efficacy: insight into nanoscale organization of signal transduction.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers.
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Who cites it
68 citing papers in PubMed, 129 citations in OpenAlex.
- Genotype-Dependent Effects of Dalcetrapib on Cholesterol Efflux and Inflammation: Concordance With Clinical Outcomes.Circulation. Cardiovascular genetics · 2016Trial
- Membrane lipid poly-unsaturation selectively affects dopamine D2 receptor endocytosis.Nature communications · 2026Article
- Effects of Membrane Cholesterol on the Structure and Function of Selected Class A GPCRs─Challenges and Future Perspectives.Biochemistry · 2025Review
- Bayesian Nonparametric Analysis of Residence Times for Protein-Lipid Interactions in Molecular Dynamics Simulations.Journal of chemical theory and computation · 2025Article
- Cholesterol inhibits assembly and oncogenic activation of the EphA2 receptor.Communications biology · 2025Article
- Cholesterol-dependent dynamic changes in the conformation of the type 1 cholecystokinin receptor affect ligand binding and G protein coupling.PLoS biology · 2024Article
- Cholesterol inhibits assembly and activation of the EphA2 receptor.bioRxiv : the preprint server for biology · 2024Article
- Molecular mechanism of GPCR spatial organization at the plasma membrane.Nature chemical biology · 2024Article
- Statin-induced increase in actin polymerization modulates GPCR dynamics and compartmentalization.Biophysical journal · 2023Article
- PI(4,5)PAdvances in experimental medicine and biology · 2023Article
- Mechanistic Insights into Membrane Protein Clustering Revealed by Visualizing EGFR Secretion.Research (Washington, D.C.) · 2022Article
- Structures of the human cholecystokinin 1 (CCK1) receptor bound to Gs and Gq mimetic proteins provide insight into mechanisms of G protein selectivity.PLoS biology · 2021Article
- Allosteric Modulation of GPCRs of Class A by Cholesterol.International journal of molecular sciences · 2021Review
- Subcellular Organization of the cAMP Signaling Pathway.Pharmacological reviews · 2021Review
- Discovery of a Positive Allosteric Modulator of Cholecystokinin Action at CCK1R in Normal and Elevated Cholesterol.Frontiers in endocrinology · 2021Article
- G-Protein-Coupled Receptor-Membrane Interactions Depend on the Receptor Activation State.Journal of computational chemistry · 2020Article
- Characterization of the Signaling Modalities of Prostaglandin E2 Receptors EP2 and EP4 Reveals Crosstalk and a Role for Microtubules.Frontiers in immunology · 2020Article
- Review
- Mouse TRPA1 function and membrane localization are modulated by direct interactions with cholesterol.eLife · 2019Article
- Regulation of monoamine transporters and receptors by lipid microdomains: implications for depression.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2018Review
8 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Determining the role of lipid raft nanodomains in G protein-coupled receptor signaling remains fraught by the lack of assays directly monitoring rafts in native membranes. We thus combined extensive biochemical and pharmacological approaches to a nanoscale strategy based on bioluminescence resonance energy transfer (BRET) to assess the spatial and functional influence of cholesterol-rich liquid-ordered lipid nanodomains on beta2 adrenergic receptor (beta2AR) signaling. The data revealed that whereas beta2AR did not partition within liquid-ordered lipid phase, a pool of G protein and adenylyl cyclase (AC) were sequestered in these domains. Destabilization of the liquid-ordered phase by cholesterol depletion led to a lateral redistribution of Galphas and AC that favored interactions between the receptor and its signaling partners as assessed by BRET. This resulted in an increased basal and agonist-promoted beta2AR-stimulated cAMP production that was partially dampened as a result of constitutive protein kinase A-dependent phosphorylation and desensitization of the receptor. This restraining influence of nanodomains on beta2AR signaling was further substantiated by showing that liquid-ordered lipid phase stabilization using caveolin overexpression or increasing membrane cholesterol amount led to an inhibition of beta2AR-associated signaling. Given the emerging concept that clustering of receptors and effectors into signaling platforms contributes to the efficacy and selectivity of signal transduction, our results support a model whereby cholesterol-promoted liquid-ordered lipid phase-embedding Gs and AC allows their lateral separation from the receptor, thus restraining the basal activity and controlling responsiveness of beta2AR signaling machinery within larger signaling platforms.
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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.