Affinage

ADRB2

Beta-2 adrenergic receptor · UniProt P07550

Round 2 corrected
Length
413 aa
Mass
46.5 kDa
Annotated
2026-04-28
130 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ADRB2 is a Gs-coupled seven-transmembrane receptor that transduces catecholamine signals into diverse intracellular responses including cAMP production, MAPK activation, and ion channel modulation across multiple cell types. Crystal structures of inactive, active, and Gs-bound ternary complex states established that agonist binding induces a 14 Å outward movement of TM6 and rearrangements in TM5/TM7, but full stabilization of the active conformation requires simultaneous G protein engagement; cholesterol and Cys341 palmitoylation contribute to receptor stability and coupling efficiency (PMID:21772288, PMID:21228869, PMID:18547522, PMID:2540197). GRK2/6-mediated phosphorylation of distinct C-tail residues encodes a barcode that differentially programs β-arrestin conformation and function—scaffolding Src-dependent ERK1/2 signaling independently of G proteins, recruiting Mdm2 for ubiquitin-dependent lysosomal degradation, and sustaining active-state signaling from endosomes (PMID:21868357, PMID:9924018, PMID:11588219, PMID:23515162). Beyond canonical Gs/cAMP signaling, ADRB2 forms macromolecular complexes with NHERF to regulate NHE3 and with Cav1.2 for localized PKA-to-channel transduction, and in non-canonical contexts controls osteoclastogenesis in mesenchymal stem cells, acts as an immunomodulatory checkpoint on T cells, and mediates neuroinflammatory lung injury via sympathetic nerve–macrophage coupling (PMID:9560162, PMID:11441182, PMID:31926929, PMID:39228124, PMID:40466637).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1987 High

    Cloning and sequencing of human ADRB2 established it as a 413-residue, seven-transmembrane protein homologous to rhodopsin, providing the primary sequence framework for all subsequent structure–function studies.

    Evidence cDNA cloning, sequencing, hydropathy analysis, and chromosomal mapping to 5q31-q32

    PMID:3025863

    Open questions at the time
    • No structural data beyond predicted transmembrane topology
    • No information on post-translational modifications
    • Functional coupling mechanism to G proteins unknown
  2. 1989 High

    Demonstration that Cys341 palmitoylation is required for efficient Gs coupling resolved how a lipid modification of the C-tail controls receptor–G protein interaction, establishing the first post-translational modification essential for ADRB2 function.

    Evidence Site-directed mutagenesis (C341G), [3H]-palmitate labeling, adenylyl cyclase and radioligand binding assays

    PMID:2540197

    Open questions at the time
    • Structural basis of palmitoylation-dependent coupling unknown
    • Whether palmitoylation affects trafficking or membrane domain partitioning was untested
  3. 1993 High

    Identification of common coding polymorphisms (Arg16Gly, Gln27Glu, Thr164Ile) in asthmatic and normal populations established that natural ADRB2 variation exists at appreciable frequency and is associated with clinical phenotypes, motivating subsequent functional characterization.

    Evidence DNA sequencing of ADRB2 from 107 subjects

    PMID:8383511

    Open questions at the time
    • Functional consequences of each polymorphism not yet defined
    • Population-level associations with disease severity not established
  4. 1994 High

    Functional dissection of Arg16Gly and Gln27Glu showed these N-terminal variants specifically regulate agonist-promoted receptor downregulation without affecting ligand binding or Gs coupling, separating degradation control from signaling competence.

    Evidence Recombinant expression in CHO cells, radioligand binding, adenylyl cyclase, and receptor downregulation assays with isoproterenol

    PMID:7915137

    Open questions at the time
    • Mechanism by which N-terminal residues control endocytic degradation unknown
    • In vivo relevance in human pharmacogenomics not yet demonstrated
  5. 1995 High

    Discovery that ADRB2 couples to Gα15/Gα16 to activate phospholipase C broadened its signaling repertoire beyond the canonical Gs/adenylyl cyclase pathway.

    Evidence Co-transfection in COS-7 cells with inositol phosphate accumulation assay

    PMID:7797501

    Open questions at the time
    • Physiological cell type where Gα15/16 coupling occurs not identified
    • Structural basis of promiscuous G protein coupling unknown
  6. 1998 High

    Identification of NHERF as a PDZ-domain-mediated binding partner of the ADRB2 C-terminus revealed how the receptor can regulate NHE3 sodium/hydrogen exchange independently of adenylyl cyclase, establishing a paradigm for GPCR-scaffolded signaling specificity.

    Evidence Co-immunoprecipitation, PDZ pulldown, C-terminal mutagenesis, NHE3 functional assay

    PMID:9560162

    Open questions at the time
    • Tissue-specific relevance of ADRB2–NHERF–NHE3 axis not defined in vivo
    • Whether NHERF competes with other C-tail interactors unresolved
  7. 1999 High

    Two studies established that β-arrestin serves as an adaptor recruiting c-Src to agonist-occupied ADRB2 to activate ERK1/2, and that EBP50/NHERF binding to the receptor tail—dependent on GRK5 phosphorylation of Ser411—is required for post-internalization recycling to the plasma membrane, revealing β-arrestin and PDZ-scaffold functions as central nodes in receptor trafficking and signaling.

    Evidence Co-IP of receptor–β-arrestin–Src, dominant-negative mutants, ERK assays; PDZ pulldown, Ser411 mutagenesis, recycling assays with fluorescence microscopy

    PMID:10499588 PMID:9924018

    Open questions at the time
    • Structural basis of β-arrestin–Src complex formation unknown
    • Competition between recycling and degradation pathways not quantified
  8. 2001 High

    Two parallel discoveries showed that (i) Mdm2-mediated ubiquitination of β-arrestin drives receptor internalization while ubiquitination of the receptor itself routes it to lysosomal degradation, and (ii) ADRB2 forms a preassembled macromolecular complex with Cav1.2, Gs, adenylyl cyclase, PKA, and PP2A enabling localized cAMP-to-channel signaling in neurons.

    Evidence Ubiquitination assays with Mdm2-null cells and lysine-less receptor mutants; Co-IP and electrophysiology in hippocampal neurons

    PMID:11441182 PMID:11588219

    Open questions at the time
    • Identity of deubiquitinases counteracting Mdm2 not yet known
    • Whether Cav1.2 complex exists in non-neuronal tissues untested
  9. 2005 High

    Genetic separation of G protein-dependent and β-arrestin-dependent ERK pathways through a G protein-uncoupled TYY mutant, combined with GRK5/6 requirement, established that ADRB2 engages two mechanistically distinct MAPK signaling modes with different kinetics.

    Evidence TYY rational mutagenesis, siRNA of β-arrestins, Gs-knockout MEFs, pertussis toxin, kinase inhibitors

    PMID:16280323

    Open questions at the time
    • Downstream transcriptional consequences of each ERK pathway arm not compared
    • In vivo relevance of β-arrestin-biased signaling not demonstrated
  10. 2007 High

    Three independent crystal structures of inactive ADRB2 (2.4–3.7 Å resolution) defined the seven-transmembrane architecture, inverse-agonist binding pocket, a hydrogen-bond network linking ligand pocket to G protein interface, and weaker TM3–TM6 ionic lock explaining higher basal activity than rhodopsin, providing the atomic framework for understanding receptor activation.

    Evidence X-ray crystallography with T4L fusion and Fab stabilization strategies; pharmacological validation

    PMID:17952055 PMID:17962519 PMID:17962520

    Open questions at the time
    • Active-state structure not yet available
    • Agonist-bound conformation unknown
    • Role of membrane lipids not resolved at atomic level
  11. 2008 High

    Identification of two specific cholesterol molecules bound per receptor between TM I–IV, with functional thermal stability enhancement, established cholesterol as a structural cofactor and predicted sterol dependence across ~44% of class A GPCRs.

    Evidence 2.8 Å crystal structure; thermal denaturation assays with cholesterol analogs

    PMID:18547522

    Open questions at the time
    • Whether cholesterol modulates signaling efficacy in cells not tested
    • Dynamics of cholesterol binding/unbinding unknown
  12. 2011 High

    A series of landmark studies resolved the activation mechanism: active-state structures (with nanobody and with Gs heterotrimer at ~3.2 Å) revealed 11–14 Å TM6 outward movement, TM5 helical extension, and major Gαs domain displacement; MD simulations showed the active state is unstable without G protein; and quantitative phosphoproteomics defined the GRK2/6-specific phosphorylation barcode on the C-tail that differentially programs β-arrestin function.

    Evidence X-ray crystallography of active and ternary complex states, 30 μs MD simulations, quantitative mass spectrometry with GRK siRNA and β-arrestin conformation BRET sensors

    PMID:21228869 PMID:21228876 PMID:21772288 PMID:21868357

    Open questions at the time
    • Full-length β-arrestin–receptor complex structure not available
    • How barcode is read by β-arrestin at atomic level unknown
    • Dynamics of Gs engagement and nucleotide exchange during signaling cycle unresolved
  13. 2012 High

    19F-NMR spectroscopy revealed that TM6 and TM7 sample distinct conformational equilibria and that biased ligands differentially perturb these equilibria—agonists shift TM6, β-arrestin-biased ligands shift TM7—providing the first structural basis for biased agonism at ADRB2.

    Evidence Site-specific 19F-NMR labeling with multiple ligand-bound receptor states

    PMID:22267580

    Open questions at the time
    • Whether TM7-biased states have distinct downstream signaling outputs in vivo not tested
    • Quantitative coupling between conformational equilibria and signaling amplitude unknown
  14. 2013 High

    Solution NMR (13C-methionine) confirmed substantial conformational heterogeneity of agonist-bound ADRB2 in the absence of G protein, while nanobody biosensors demonstrated that ADRB2 remains active on early endosomes after internalization and contributes to cellular cAMP production, establishing endosomal signaling as a physiologically relevant signaling compartment.

    Evidence Solution NMR with multiple ligand states; live-cell conformational nanobody biosensors with FRET and cAMP measurement; multiple active-state crystal structures with endogenous adrenaline

    PMID:23374348 PMID:23515162 PMID:24056936

    Open questions at the time
    • Duration and regulation of endosomal signaling not quantified
    • Whether endosomal signaling engages distinct transcriptional programs from plasma membrane signaling unclear
  15. 2014 Medium

    ADRB2 was placed in a mechanosensitive osteoclastogenesis pathway: mechanical force upregulates ADRB2 in periodontal ligament cells, which increases RANKL/OPG to drive osteoclast differentiation; ADRB1/2 knockout mice show reduced tooth movement, extending ADRB2 function to bone remodeling.

    Evidence Mechanical force application, Ca2+ imaging, RANKL/OPG ratio, ADRB1/2 knockout mice, co-culture osteoclastogenesis

    PMID:25252876

    Open questions at the time
    • ADRB2-specific contribution not separated from ADRB1 in the double knockout
    • Downstream signaling cascade from ADRB2 to RANKL transcription not fully delineated
  16. 2020 Medium

    Conditional deletion of ADRB2 in nestin+ MSCs attenuated subchondral bone loss in osteoarthritis, demonstrating a cell-type-specific role for ADRB2 in MSC-driven osteoclast differentiation and aberrant calcification at the osteochondral interface.

    Evidence Nestin-Cre × ADRB2-flox conditional knockout mice, micro-CT, histomorphometry

    PMID:31926929

    Open questions at the time
    • Molecular pathway downstream of ADRB2 in MSCs not fully resolved
    • Relevance to human osteoarthritis not established
  17. 2022 Medium

    ERAP1 was identified as a direct ADRB2-interacting protein that reduces receptor levels by suppressing USP33-mediated deubiquitination, linking a circulating hepatokine to impaired ADRB2-dependent insulin signaling in skeletal muscle and systemic insulin resistance.

    Evidence Co-IP of ERAP1–ADRB2, USP33 deubiquitination assay, hepatic ERAP1 overexpression/knockdown, high-fat diet mouse model with insulin tolerance tests

    PMID:35192681

    Open questions at the time
    • Structural basis of ERAP1–ADRB2 interaction unknown
    • Whether ERAP1 affects ADRB2 in tissues other than skeletal muscle not tested
  18. 2024 Medium

    ADRB2 was identified as an inhibitory checkpoint on T cells: its knockdown in CAR-T cells enhanced cytotoxicity, proliferation, and central memory formation via the ZAP-70/NF-κB axis, repositioning ADRB2 as an immunosuppressive receptor in anti-tumor immunity.

    Evidence shRNA knockdown in CAR-T cells, ZAP-70/NF-κB pathway analysis, prostate cancer xenograft model

    PMID:39228124

    Open questions at the time
    • Mechanism by which ADRB2 suppresses ZAP-70 phosphorylation not defined
    • Whether this is relevant to endogenous T cell responses beyond CAR-T not tested
    • Single study without independent replication
  19. 2025 Medium

    ADRB2+ interstitial macrophages surrounding pulmonary sympathetic nerves were identified as effectors of a brain-to-lung neuroinflammatory circuit: catecholamines released via a CeA–RVLM–sympathetic pathway activate macrophage ADRB2 to amplify inflammatory cytokine production and lung injury during severe pneumonia.

    Evidence Chemogenetic inhibition of CeA neurons, sympathetic nerve ablation, ADRB2 inhibition, single-cell identification of ADRB2+ macrophages, mouse pneumonia model

    PMID:40466637

    Open questions at the time
    • Human relevance of this neural–immune circuit not established
    • Whether ADRB2 macrophage signaling uses canonical Gs/cAMP or alternative pathway not defined
    • Single study in mouse pneumonia model

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the high-resolution structure of the full ADRB2–β-arrestin complex, the atomic mechanism by which the GRK phosphorylation barcode is decoded by β-arrestin, the quantitative contribution of endosomal versus plasma membrane signaling to physiological outcomes in specific tissues, and the molecular basis of ADRB2-mediated immunomodulation on T cells.
  • No ADRB2–β-arrestin co-structure available
  • Endosomal signaling contribution not quantified in vivo
  • Structural basis of ERAP1–ADRB2 interaction unknown
  • T cell immunomodulatory mechanism not mechanistically resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 2 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-168256 Immune System 2
Partners
ARRB1ARRB2GNASGRK2GRK6MDM2SLC9A3R1SRC
Complex memberships
ADRB2–Cav1.2–AC–PKA–PP2A macromolecular complexADRB2–Gs heterotrimer signaling complexADRB2–NHERF/EBP50 complexADRB2–β-arrestin–Src complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1987 The human ADRB2 cDNA was isolated and sequenced, revealing a 413-residue protein with seven hydrophobic membrane-spanning domains homologous to rhodopsin/opsins. The gene was localized to chromosome 5q31-q32. cDNA cloning, sequencing, hydropathy analysis, chromosomal mapping Proceedings of the National Academy of Sciences of the United States of America High 3025863
1989 Cys341 in the carboxyl tail of the human β2-adrenergic receptor is palmitoylated; mutation of Cys341 to glycine abolishes palmitoylation and drastically reduces agonist-stimulated adenylyl cyclase activation and high-affinity guanyl nucleotide-sensitive agonist binding, demonstrating that palmitoylation is required for normal G protein coupling. Site-directed mutagenesis, [3H]-palmitate labeling, adenylyl cyclase assay, radioligand binding The Journal of biological chemistry High 2540197
1993 Nine naturally occurring point mutations were identified in the ADRB2 gene in asthmatic and normal subjects, including four amino acid changes (Arg16Gly, Gln27Glu, Val34Met, Thr164Ile). Arg16Gly was the most frequent polymorphism and identified a clinical subset of asthma patients, establishing that ADRB2 coding variants exist at appreciable frequency. DNA sequencing of ADRB2 gene from 51 asthmatic and 56 normal subjects; functional inference from known receptor biology American journal of respiratory cell and molecular biology High 8383511
1994 The Arg16Gly polymorphism of ADRB2 increases agonist-promoted receptor downregulation, whereas the Gln27Glu polymorphism renders the receptor completely resistant to downregulation; both polymorphisms leave agonist binding and Gs coupling intact, indicating that residues 16 and 27 in the extracellular N-terminus specifically regulate agonist-promoted receptor degradation. Site-directed mutagenesis, recombinant expression in CHO fibroblasts, radioligand binding, adenylyl cyclase assay, receptor downregulation assay with isoproterenol Biochemistry High 7915137
1995 The β2-adrenergic receptor couples to and activates Gα15/Gα16 to stimulate phospholipase C-mediated inositol phosphate production, demonstrating that ADRB2 can signal through non-canonical G protein pathways beyond Gs. Co-transfection of ADRB2 with Gα15/Gα16 in COS-7 cells, inositol phosphate assay The Journal of biological chemistry High 7797501
1998 The β2-adrenergic receptor directly associates with the Na+/H+ exchanger regulatory factor (NHERF) via a PDZ-domain interaction with the C-terminal residues of the receptor (last leucine critical); this agonist-promoted interaction is required for β2AR-mediated regulation of NHE3 activity but not adenylyl cyclase activation. Co-immunoprecipitation, PDZ-domain pulldown, site-directed mutagenesis (L→A at C-terminus), NHE3 functional assay Nature High 9560162
1999 β-Arrestin acts as an adapter protein that recruits activated c-Src to the agonist-occupied β2-adrenergic receptor, forming a receptor–β-arrestin–Src complex; this complex mediates activation of ERK1/2 MAP kinases, and β-arrestin1 mutants defective in either Src binding or clathrin-pit targeting act as dominant-negative inhibitors of β2AR-stimulated ERK activation. Co-immunoprecipitation, dominant-negative mutant expression, MAP kinase activation assay, clathrin-pit targeting assay Science High 9924018
1999 EBP50 binds to the C-terminal cytoplasmic tail of the β2-adrenergic receptor via a PDZ-domain interaction; this interaction, together with EBP50 binding to the cortical actin cytoskeleton via its ERM-binding domain, is required for proper recycling of internalized β2AR to the plasma membrane. GRK5 phosphorylation of Ser411 in the receptor tail is required for EBP50 binding and hence receptor recycling. PDZ-domain pulldown, dominant-negative disruption, site-directed mutagenesis (Ser411), transferrin receptor recycling controls, fluorescence microscopy Nature High 10499588
2001 Agonist stimulation of β2AR leads to rapid ubiquitination of both the receptor and β-arrestin; β-arrestin recruits the E3 ubiquitin ligase Mdm2 and acts as an adapter for receptor ubiquitination. β-Arrestin ubiquitination (by Mdm2) is required for efficient receptor internalization, whereas receptor ubiquitination itself is required for lysosomal degradation but not internalization. Ubiquitination assay, Mdm2-null cells, dominant-negative Mdm2 expression, receptor internalization and degradation assays, lysine-less receptor mutant Science High 11588219
2001 The β2-adrenergic receptor is directly associated with the L-type calcium channel Cav1.2, forming a macromolecular signaling complex that also includes a G protein, adenylyl cyclase, PKA, and phosphatase PP2A; this pre-assembled complex enables highly localized and specific β2AR-to-channel signal transduction in hippocampal neurons. Co-immunoprecipitation, direct binding assay, electrophysiology in hippocampal neurons Science High 11441182
2005 β2AR signals to ERK1/2 through two distinct pathways: a rapid, transient Gs/Gi/PKA-dependent pathway and a slower, more sustained β-arrestin-dependent, G protein-independent pathway. A rationally designed β2AR mutant (TYY) incapable of G protein activation retained β-arrestin recruitment and β-arrestin-dependent ERK activation; GRK5/6 (but not GRK2 without plasma membrane anchoring) mediated this β-arrestin-dependent ERK signaling. siRNA knockdown of β-arrestins, Gs-knockout MEFs, rational mutagenesis (TYY mutant), pertussis toxin, kinase inhibitors, ERK phosphorylation assay The Journal of biological chemistry High 16280323
2007 Crystal structure of human β2AR-T4L fusion at 2.4 Å resolution (with inverse agonist carazolol) revealed the seven-transmembrane bundle architecture, the ligand-binding pocket accessed via the second extracellular loop (held by disulfide bridges), and a specific cholesterol-mediated parallel receptor association in the crystal lattice. X-ray crystallography at 2.4 Å; β2AR-T4L fusion protein strategy Science (New York, N.Y.) High 17962520
2007 Engineering β2AR with T4L replacing the third intracellular loop (β2AR-T4L) retains near-native pharmacology; the crystal structure at 2.4 Å defined the inverse-agonist binding site and revealed a hydrogen-bond network linking the ligand pocket to regions that interact with G proteins, providing mechanistic insight into inverse-agonist binding. GPCR engineering, radioligand binding, adenylyl cyclase assay, X-ray crystallography Science (New York, N.Y.) High 17962519
2007 Crystal structure of human β2AR at 3.4/3.7 Å (in lipid, with inverse agonist and anti-third-intracellular-loop Fab) showed that the cytoplasmic ends of TM3 and TM6 have weaker interactions (via E/DRY) than in rhodopsin, correlating with higher basal activity and structural instability of β2AR. X-ray crystallography in lipidic environment, microcrystallography Nature High 17952055
2008 A 2.8 Å crystal structure of thermally stabilized β2AR revealed two specific cholesterol molecules bound per receptor between helices I, II, III, and IV (not in the packing interface), identifying a structurally relevant cholesterol-binding site. Cholesterol binding significantly enhances receptor thermal stability. A consensus cholesterol-binding motif predicts sterol binding in 44% of human class A GPCRs. X-ray crystallography at 2.8 Å, isothermal denaturation/thermal stability assay with cholesterol analog Structure (London, England : 1993) High 18547522
2011 Crystal structure of active-state β2AR bound to a covalent agonist (β2AR-T4L, 3.5 Å) shows that stabilization of the active conformation requires binding events at both extracellular (agonist) and intracellular (G protein or antibody) surfaces; MD simulations show the agonist-bound active conformation spontaneously relaxes to inactive in the absence of G protein. X-ray crystallography (3.5 Å), molecular dynamics simulations (up to 30 μs), covalent agonist design Nature High 21228876
2011 Crystal structure of active-state β2AR stabilized by a G-protein-mimetic nanobody (BI167107-bound, 3.5 Å) shows an 11 Å outward movement of the cytoplasmic end of TM6 and rearrangements of TM5 and TM7 compared with inactive state, remarkably similar to active opsin. Agonist alone does not fully stabilize the active conformation. Camelid nanobody generation, X-ray crystallography (3.5 Å), comparison with inactive β2AR structure Nature High 21228869
2011 Crystal structure of the β2AR–Gs heterotrimer complex (active ternary complex, ~3.2 Å) revealed that the principal β2AR–Gs interactions involve the α5 and αN helices of Gαs, with a 14 Å outward movement at TM6 cytoplasmic end and α-helical extension of TM5; a major displacement of the α-helical domain of Gαs relative to the Ras-like domain was observed—the first high-resolution view of transmembrane GPCR signaling. X-ray crystallography of ternary complex, nanobody stabilization Nature High 21772288
2011 Individual GRKs (GRK2 vs. GRK6) phosphorylate distinct serine/threonine residues on the β2AR C-terminal tail, establishing a 'phosphorylation barcode' that imparts distinct conformations to recruited β-arrestin and thereby differentially controls β-arrestin functions (desensitization, internalization, ERK signaling). Quantitative mass spectrometry mapping of phosphorylation sites, siRNA of GRK2/GRK6, β-arrestin conformation BRET sensors, ERK assay Science signaling High 21868357
2012 19F-NMR of site-specifically labeled β2AR revealed that the cytoplasmic ends of helices VI and VII exist in two major conformational states; agonist binding primarily shifts TM6 equilibrium toward the G protein-active state, whereas β-arrestin-biased ligands predominantly impact TM7 conformational states, providing a structural basis for biased agonism. Site-specific 19F-NMR labeling of β2AR in defined ligand complexes Science (New York, N.Y.) High 22267580
2013 NMR spectroscopy (13CH3ε-methionine labeling) showed that β2AR exists in substantial conformational heterogeneity even when bound to agonist; unlike rhodopsin, agonist alone does not stabilize the fully active conformation of β2AR—G protein or G-protein-mimetic nanobody is additionally required, consistent with a flexible allosteric coupling between ligand-binding pocket and G protein-coupling surface. Solution NMR (HSQC spectra), 13C-methionine labeling, multiple ligand states including inverse agonist, agonist, and nanobody Cell High 23374348
2013 Conformation-specific nanobodies used as biosensors in living cells showed that the β2-adrenoceptor is activated not only at the plasma membrane but also in the early endosome membrane following agonist-induced internalization, and that endosome-localized β2AR contributes to the overall cellular cAMP response within minutes after agonist application. Conformational nanobody biosensors, live-cell fluorescence imaging, FRET, cAMP measurement Nature High 23515162
2013 Crystal structures of active-state human β2AR bound to three chemically distinct agonists (BI167107, hydroxybenzyl isoproterenol, and native adrenaline) showed a conserved ligand-recognition and activation mode; the adrenaline-bound structure revealed substantial rearrangements in extracellular loop 3 and the extracellular tip of TM6, and identified a water-mediated hydrogen bond between two conserved tyrosines that stabilizes the active state. Directed evolution of high-affinity camelid nanobody, X-ray crystallography of multiple agonist-bound structures Nature High 24056936
2011 Atomic-level MD simulations of β2AR (up to 30 μs) revealed a loosely coupled allosteric network of three regions linking small extracellular perturbations to large intracellular conformational changes; the simulations identified an intermediate conformation that may represent the G protein pre-coupling state, and suggested that the first structural changes during activation can occur on the intracellular side of the receptor. Long-timescale molecular dynamics simulation (~30 μs), comparison with crystal structures Proceedings of the National Academy of Sciences of the United States of America Medium 22031696
2014 Mechanical compressive force upregulates ADRB2 expression in human periodontal ligament cells (PDLCs) via elevation of intracellular Ca2+; ADRB2 activation in PDLCs increases the RANKL/OPG ratio and promotes osteoclastogenesis from co-cultured peripheral blood mononuclear cells, thereby accelerating orthodontic tooth movement. ADRB1/2 knockout mice showed markedly reduced tooth movement in vivo. Mechanical force application in vitro/in vivo, Ca2+ imaging, RANKL/OPG ratio measurement, co-culture osteoclastogenesis assay, ADRB1/2 knockout mouse model, RT-PCR, western blotting Journal of dental research Medium 25252876
2019 PM2.5 exposure causes ADRB2 promoter hypermethylation in cardiomyocytes, reducing β2AR expression, which inhibits PI3K/Akt signaling and activates Bcl-2/BAX and p53 apoptosis pathways. Overexpression of ADRB2 attenuates PM2.5-induced apoptosis, and this protection is reversed by PI3K inhibitor LY294002, placing ADRB2 upstream of PI3K/Akt in a cardioprotective pathway. Methylation chip, bisulfite sequencing PCR, ADRB2 transgenic cell lines, PI3K inhibitor treatment, TUNEL assay, western blotting, in vivo rat instillation model with echocardiography Environment international Medium 30986742
2019 ADRB2 activation by stress hormones (epinephrine, norepinephrine) promotes gastric cancer cell proliferation, invasion, and tumor growth via the ERK1/2-JNK-MAPK pathway and transcription factors NF-κB, AP-1, CREB and STAT3; selective ADRB2 antagonist ICI118,551 blocked these effects and suppressed expression of VEGF, MMP-2, MMP-7, and MMP-9. Cell proliferation, migration, invasion assays; xenograft models; ADRB2-specific agonist/antagonist treatment; ERK1/2, NF-κB, STAT3 pathway analysis; immunohistochemistry Cell death & disease Medium 31624248
2020 Conditional deletion of ADRB2 in nestin+ mesenchymal stem cells (MSCs) largely attenuated subchondral bone loss and cartilage degradation in a temporomandibular joint osteoarthritis model, demonstrating that ADRB2 signaling in MSCs promotes osteoclast differentiation (via elevated pro-osteoclastic factors) and aberrant calcification at the osteochondral interface. Nestin-Cre × ADRB2-flox conditional knockout mice, unilateral anterior crossbite model, micro-CT, histomorphometry, immunostaining Bone Medium 31926929
2022 ERAP1 (a hepatokine upregulated by high-fat diet and inflammation) interacts directly with β2-adrenergic receptor (ADRB2) and reduces its expression by decreasing USP33 (ubiquitin-specific peptidase 33)-mediated deubiquitination, thereby interrupting ADRB2-stimulated insulin signaling in skeletal muscle and impairing insulin sensitivity. Co-immunoprecipitation of ERAP1-ADRB2, hepatic ERAP1 overexpression/knockdown, USP33 deubiquitination assay, insulin tolerance tests, high-fat diet mouse model Diabetes Medium 35192681
2024 ADRB2 functions as an inhibitory checkpoint on T cells; knockdown of ADRB2 in CAR-T cells enhanced cytotoxicity, proliferation, CD8/CD4 ratio, Bcl-2 expression, and central memory generation via the ZAP-70/NF-κB signaling axis, and improved tumor eradication in prostate cancer xenograft models. shRNA knockdown of ADRB2 in CAR-T cells, cytotoxicity assay, flow cytometry, western blotting for ZAP-70/NF-κB pathway, in vivo xenograft model Molecular therapy Medium 39228124
2025 A subpopulation of ADRB2+ interstitial macrophages surrounding pulmonary sympathetic nerves responds to norepinephrine released via a CeA-RVLM-sympathetic neural pathway during severe pneumonia; activation of ADRB2 on these macrophages amplifies inflammatory cytokine production and lung injury, identifying ADRB2 as a key node in brain-to-lung neuroinflammatory signaling. Chemogenetic inhibition of CeA GABAergic neurons, sympathetic nerve ablation, specific ADRB2 inhibition in vivo, single-cell identification of ADRB2+ macrophages, norepinephrine measurement, cytokine assays, survival studies in mouse pneumonia model Immunity Medium 40466637

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science (New York, N.Y.) 2624 17962520
2011 Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature 2471 21772288
2007 Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature 1509 17952055
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2011 Structure of a nanobody-stabilized active state of the β(2) adrenoceptor. Nature 1408 21228869
2003 BAR domains as sensors of membrane curvature: the amphiphysin BAR structure. Science (New York, N.Y.) 1388 14645856
1999 Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes. Science (New York, N.Y.) 1258 9924018
2007 GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function. Science (New York, N.Y.) 1130 17962519
2001 Molecular phylogenetics and the origins of placental mammals. Nature 862 11214319
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2002 Identification of membrane-type receptor for bile acids (M-BAR). Biochemical and biophysical research communications 812 12419312
2008 A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor. Structure (London, England : 1993) 780 18547522
2001 Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin. Science (New York, N.Y.) 695 11588219
2013 Conformational biosensors reveal GPCR signalling from endosomes. Nature 677 23515162
2013 The dynamic process of β(2)-adrenergic receptor activation. Cell 658 23374348
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1987 cDNA for the human beta 2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor. Proceedings of the National Academy of Sciences of the United States of America 655 3025863
1994 Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 645 7915137
2011 Structure and function of an irreversible agonist-β(2) adrenoceptor complex. Nature 637 21228876
2005 beta-arrestin-dependent, G protein-independent ERK1/2 activation by the beta2 adrenergic receptor. The Journal of biological chemistry 629 16280323
2012 Biased signaling pathways in β2-adrenergic receptor characterized by 19F-NMR. Science (New York, N.Y.) 572 22267580
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