Affinage

Showing CNR2 — CB2 is a alias.

CNR2

Cannabinoid receptor 2 · UniProt P34972

Length
360 aa
Mass
39.7 kDa
Annotated
2026-06-09
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CNR2/CB2 is a Gi/o-coupled cannabinoid receptor that transduces endocannabinoid signals predominantly in immune and peripheral tissues, classically inhibiting adenylyl cyclase and activating ERK1/2 MAPK (PMID:9336020, PMID:12084572). Through its Gi output CB2 drives a mitogenic axis in osteoblasts coupling ERK1/2, MAPKAPK2, and CREB to cyclin D1 transcription, and genetically governs bone homeostasis by promoting osteoblast activity while restraining osteoclastogenesis (PMID:16407142, PMID:20803555). Depending on cell context CB2 signals through additional effector arms—PI3K/Akt to drive neural stem cell and germ cell proliferation (PMID:17328768, PMID:19541620), AMPK/CREB/BDNF for neuroprotection (PMID:23414569), and β-arrestin2/ERK-PI3K/AKT/GSK-3β converging on Nurr1 to suppress microglial phagocytosis (PMID:35132190). CB2 ligands are strongly functionally selective, with classic cannabinoids and endocannabinoids biased toward G-protein signaling over arrestin recruitment (PMID:27194477). In immune cells CB2 is broadly anti-inflammatory: it enhances CD40-driven B-cell proliferation (PMID:9808554), dampens NF-κB/NFAT and promotes IL-10/Treg responses in T cells (PMID:25980325), limits leukocyte-driven tissue fibrosis (PMID:19333940), and directly binds JAK1 to inhibit STAT signaling and suppress tumor-specific T-cell function (PMID:35383142). CB2 forms functionally distinct heteromers with CB1, GPR55, HER2, and CXCR4 that reshape downstream signaling, including cross-antagonism with CB1, modulation of GPR55 transcription-factor output, HER2 pro-oncogenic feedback, and inhibition of CXCR4-driven migration via Gα13/RhoA (PMID:22532560, PMID:25048571, PMID:25855725, PMID:29330286). In the nervous system CB2 also modulates axon guidance through a PKA-DCC mechanism (PMID:23951024), and peripheral sensory-neuron CB2 specifically mediates antinociception and morphine-tolerance sparing (PMID:16563625, PMID:36417942). Crystal and cryo-EM structures define the CB2 orthosteric pocket, the molecular basis of CB1/CB2 selectivity, and a lipophilic TM1-TM7 membrane-access channel used by endocannabinoids (PMID:30639103, PMID:36922494).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1997 High

    Established the foundational identity of CB2 as a Gi-coupled receptor with a peripheral/immune distribution and adenylyl cyclase inhibition as a core effector, defining the receptor's basic signaling logic.

    Evidence Pharmacological characterization, radioligand binding, and effector assays

    PMID:9336020

    Open questions at the time
    • Did not define downstream kinase cascades
    • Did not resolve cell-type-specific functions
  2. 1998 High

    Demonstrated CB2 is functionally engaged in immune cell biology, showing receptor-selective enhancement of CD40-mediated B-cell proliferation during differentiation.

    Evidence Anti-CB2 immunostaining, flow cytometry, and proliferation assays with CB2- vs CB1-selective antagonists

    PMID:9808554

    Open questions at the time
    • Signaling pathway linking CB2 to proliferation not defined
    • In vivo relevance to humoral immunity untested
  3. 2002 Medium

    Identified MAPK/ERK activation as a direct CB2 signaling output, extending the effector repertoire beyond cyclase inhibition.

    Evidence Stable rat CB2 expression in CHO cells with MAPK activation assay

    PMID:12084572

    Open questions at the time
    • Single heterologous system
    • G-protein dependence not dissected
  4. 2006 High

    Genetic and pharmacological evidence placed CB2 at the center of bone homeostasis and in vivo antinociception, two of its defining physiological roles.

    Evidence CB2 knockout mice with histomorphometry, ovariectomy and bone cell models, and thermal nociception with CB2-selective agonist AM1241

    PMID:16407142 PMID:16563625

    Open questions at the time
    • Intracellular mechanism in bone cells not yet resolved
    • Cell type mediating antinociception not localized
  5. 2007 Medium

    Linked CB2 to proliferative control in neural and germ-cell lineages, identifying PI3K/Akt and ERK1/2 as proliferative effector arms under endogenous endocannabinoid tone.

    Evidence Neurosphere cultures with PI3K/Akt inhibitor and selective pharmacology; primary spermatogonia with ERK phosphorylation and meiotic markers (2009)

    PMID:17328768 PMID:19541620

    Open questions at the time
    • Reliance on pharmacology rather than genetic deletion in these systems
    • Endocannabinoid identity inferred
  6. 2009 High

    Bone marrow transplantation epistasis established that leukocyte-expressed CB2 is the cell-autonomous source restraining tissue fibrosis, distinguishing immune from parenchymal CB2.

    Evidence CB2 knockout, bleomycin fibrosis model, and reciprocal bone marrow transplantation

    PMID:19333940

    Open questions at the time
    • Specific leukocyte subset not identified
    • Downstream anti-fibrotic mediators undefined
  7. 2011 High

    Resolved the CB2 mitogenic mechanism in osteoblasts as a Gi-ERK1/2-MAPKAPK2-CREB-cyclin D1 axis, providing a defined pathway for CB2-driven proliferation.

    Evidence Osteoblast cultures with pertussis toxin, MEK inhibitors, Mapkapk2 siRNA, and CREB reporter assays

    PMID:20803555

    Open questions at the time
    • Generalizability of this axis to other proliferative tissues untested
  8. 2012 High

    Demonstrated that CB2 oligomerizes with other receptors to generate novel signaling units, beginning with CB1-CB2 heteromers showing bidirectional cross-antagonism and negative Akt cross-talk.

    Evidence BRET, FRET, Co-IP in transfected cells and rat brain with Akt and neurite outgrowth readouts

    PMID:22532560

    Open questions at the time
    • Stoichiometry and structural interface unresolved
    • Physiological consequence in native circuits limited
  9. 2013 High

    Expanded CB2's context-dependent signaling and partner network: AMPK/CREB neuroprotection, T-cell immunosuppression via NF-κB/NFAT and IL-10/Tregs, GPR55 heteromer signaling rewiring, and PKA-DCC-dependent axon guidance.

    Evidence OGD/R neuron models, CB2-KO T cells in mixed lymphocyte reactions, Co-IP/BRET for GPR55 heteromers, and cnr2-KO retino-thalamic tracing

    PMID:23414569 PMID:23951024 PMID:25048571 PMID:25980325

    Open questions at the time
    • Which effector arm dominates is cell-context specific and not unified
    • Heteromer interfaces not structurally defined
  10. 2015 High

    Established bidirectional HER2-CB2 cross-regulation in cancer, where HER2 induces CB2 via ERK-ELK1 and CB2 in turn amplifies HER2 oncogenic signaling through c-SRC.

    Evidence siRNA/shRNA, overexpression, Co-IP, PLA, and MMTV-neu;CB2-KO mouse model

    PMID:25855725

    Open questions at the time
    • Heteromer structural basis undefined
    • Therapeutic exploitability untested
  11. 2016 High

    Systematically defined CB2 ligand functional selectivity, showing classic cannabinoids and endocannabinoids are G-protein biased while aminoalkylindoles recruit arrestin, framing biased agonism as a design principle.

    Evidence Adenylyl cyclase inhibition and BRET β-arrestin recruitment assays across a structurally diverse ligand panel

    PMID:27194477

    Open questions at the time
    • Structural basis of bias not resolved in this study
    • Physiological consequence of bias in vivo not addressed
  12. 2018 Medium

    Showed CB2-CXCR4 heterodimerization suppresses chemokine-driven migration and invasion via inhibition of the Gα13/RhoA cytoskeletal axis.

    Evidence Co-IP, colocalization, migration/invasion/adhesion assays, and Gα13/RhoA Western blots

    PMID:29330286

    Open questions at the time
    • Single lab
    • Direct interface and in vivo relevance limited
  13. 2019 High

    Provided the first atomic structure of CB2 (antagonist-bound crystal), revealing a distinct binding pose from CB1 and the molecular determinants of CB1/CB2 selectivity.

    Evidence 2.8 Å X-ray crystallography with site-directed mutagenesis and molecular docking

    PMID:30639103

    Open questions at the time
    • Antagonist-bound state only
    • Active-state and G-protein coupling not captured
  14. 2022 High

    Identified a non-canonical CB2 mechanism—direct JAK1 binding that suppresses STAT signaling—explaining cannabinoid impairment of tumor-specific T-cell function, and localized antinociceptive CB2 to peripheral sensory neurons.

    Evidence FLAG-Cnr2 knock-in mouse with FLAG pulldown of JAK1 and STAT assays; advillinCre;CB2f/f conditional knockout with neuropathic pain and morphine tolerance assays

    PMID:35383142 PMID:36417942

    Open questions at the time
    • Whether JAK1 binding is G-protein-independent not fully resolved
    • Structural basis of CB2-JAK1 interaction undefined
  15. 2022 Medium

    Defined the CB2-Nurr1 axis in microglia, where β-arrestin2/ERK and PI3K/AKT/GSK-3β signaling drive Nurr1 nuclear translocation to inhibit phagocytosis.

    Evidence BV-2 and primary microglia with pathway inhibitors, Nurr1 overexpression, nuclear fractionation, and phagocytosis assays

    PMID:35132190

    Open questions at the time
    • Single lab
    • In vivo microglial relevance not established
  16. 2023 High

    Cryo-EM of agonist-bound CB2 captured the active-state pocket and revealed a TM1-TM7 membrane channel through which lipophilic endocannabinoids access the binding site, unifying structural and pharmacological selectivity.

    Evidence Cryo-EM with multiple agonists, mutagenesis, binding kinetics, and in vivo nephropathy pharmacology

    PMID:36922494

    Open questions at the time
    • Heteromer structures not resolved
    • Biased signaling structural states not separately captured
  17. 2024 Medium

    Demonstrated that engaging both protomers of the CB2 homodimer with a homobivalent ligand modulates dimerization dynamics to enhance both Gi signaling and arrestin recruitment, indicating dimer-level allosteric control.

    Evidence Computational docking, BRET homodimerization, Gi signaling, and β-arrestin recruitment assays

    PMID:39179054

    Open questions at the time
    • Single lab
    • Structural confirmation of bivalent binding mode pending

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CB2's many context-specific effector arms (Gi/cyclase, ERK, PI3K/Akt, AMPK/CREB, β-arrestin/Nurr1, JAK1/STAT) and its diverse heteromers are selected and integrated in a given cell type remains unresolved.
  • No unifying model linking ligand bias to cell-type-specific effector choice
  • Structural basis of CB2 heteromers undefined
  • Endogenous regulation of CB2-JAK1 versus G-protein coupling unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4
Partners
CNR1CXCR4ERBB2GPR55JAK1
Complex memberships
CB1-CB2 heteromerCB2-CXCR4 heterodimerCB2-GPR55 heteromerHER2-CB2 heteromer

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 CB2 (CNR2) is a G protein-coupled receptor that couples to Gi proteins; its effector systems include inhibition of adenylyl cyclase. CB2 receptors are present in peripheral tissues and immune system. Pharmacological characterization, radioligand binding, effector assays Pharmacology & therapeutics High 9336020
1998 CB2 receptor expression is downregulated during B-cell differentiation (lowest in germinal center centroblasts), and CB2 receptor activation by cannabinoid agonist CP55,940 enhanced CD40-mediated B-cell proliferation, an effect blocked by CB2 antagonist SR 144528 but not CB1 antagonist SR 141716, demonstrating functional CB2 signaling in B-cell differentiation. Immunopurified anti-CB2 antibodies, dual-color confocal microscopy, flow cytometry, proliferation assays with selective antagonists Blood High 9808554
2002 Rat CB2 (rCB2) activates mitogen-activated protein kinase (MAPK/ERK) when stably expressed in CHO cells, establishing a direct signaling output of CB2 receptor activation. Stable expression in CHO cells, MAPK activation assay Biochimica et biophysica acta Medium 12084572
2002 Functional, epitope-tagged CB2 receptor was expressed in Pichia pastoris with pharmacological binding profile similar to mammalian-expressed receptor, and purified receptor was characterized by MALDI/TOF and ESI mass spectrometry. Heterologous expression in P. pastoris, radioligand binding, metal chelating chromatography, MALDI/TOF and ESI mass spectrometry Protein expression and purification Medium 12460775
2006 CB2-deficient mice show accelerated age-related trabecular bone loss with increased osteoclast numbers and decreased osteoblast precursors; CB2 is expressed in osteoblasts, osteocytes, and osteoclasts. A CB2-specific agonist enhances osteoblast number/activity and restrains osteoclastogenesis by inhibiting osteoclast precursor proliferation and RANKL expression in bone marrow-derived osteoblasts/stromal cells, and attenuates ovariectomy-induced bone loss. CB2 knockout mice, histomorphometry, pharmacological agonist treatment, ovariectomy model, bone cell culture assays Proceedings of the National Academy of Sciences of the United States of America High 16407142
2006 CB2 receptor activation by AM1241 produces antinociception in wild-type mice but has no effect in CB2 knockout mice, demonstrating that antinociceptive effects of AM1241 are mediated specifically through CB2 receptors in vivo. CB2 knockout mice vs. wild-type, thermal nociception assay, pharmacological challenge Pain High 16563625
2007 CB2 receptor activation in neural stem/precursor cells (neurospheres) stimulates proliferation via a phosphoinositide-3 kinase (PI3K)/Akt signaling pathway; selective CB2 agonist JWH-056 stimulates neurosphere formation, and CB2 antagonist SR-144528 blocks basal proliferation, indicating endogenous cannabinoid tone through CB2. Neurosphere cultures, BrdU incorporation, pharmacological agonists/antagonists, PI3K/Akt inhibitor (BML-257) The European journal of neuroscience Medium 17328768
2009 CB2 receptor activation by selective agonist JWH133 induced ERK1/2 MAPK phosphorylation in spermatogonia and promoted their progression toward meiosis, increasing cells positive for meiotic marker SCP3 and early meiotic prophase gene expression; endogenous 2-AG (higher in mitotic germ cells) is the likely endocannabinoid signal acting through CB2 during spermatogenesis. Purified germ cell fractions, primary spermatogonia cultures, selective CB2 agonist, Western blot (ERK phosphorylation), immunostaining for SCP3, RT-PCR for meiotic genes Proceedings of the National Academy of Sciences of the United States of America High 19541620
2009 CB2 limits leukocyte infiltration and tissue fibrosis in experimental dermal fibrosis; the fibrosis-suppressing effect is mediated by leukocyte-expressed CB2, as shown by bone marrow transplantation: CB2-/- bone marrow transplanted into wild-type mice recapitulated increased fibrosis, while wild-type marrow into CB2-/- mice rescued the phenotype. CB2 knockout mice, bleomycin-induced fibrosis model, pharmacological agonist/antagonist treatment, bone marrow transplantation, histology Arthritis and rheumatism High 19333940
2011 CB2 receptor signals through a Gi protein-cyclin D1 mitogenic axis in osteoblasts: CB2 activation stimulates ERK1/2 phosphorylation, de novo synthesis of MAPKAPK2, CREB transcriptional activation, and cyclin D1 mRNA expression; these effects are blocked by pertussis toxin (Gi inhibitor), MEK-ERK1/2 inhibitors, and Mapkapk2 siRNA. Osteoblast cultures (MC3T3 E1 and primary calvarial), selective CB2 agonists, Western blot, RT-PCR, CREB reporter assay, Mapkapk2 siRNA knockdown, pertussis toxin treatment Journal of bone and mineral research High 20803555
2012 CB2 and CB1 receptors form functional heteromers in transfected neuronal cells and in rat brain (pineal gland, nucleus accumbens, globus pallidus). Within CB1-CB2 heteromers, co-activation produces negative cross-talk in Akt phosphorylation and neurite outgrowth. CB1 antagonists block CB2 agonist effects and vice versa (bidirectional cross-antagonism), a property unique to the heteromeric complex. BRET, FRET, co-immunoprecipitation in transfected cells and rat brain tissue, Akt phosphorylation assay, neurite outgrowth assay, pharmacological cross-antagonism The Journal of biological chemistry High 22532560
2013 CB2 receptor activation by trans-caryophyllene (TC) reduced ischemic neuronal injury through AMPK/CREB signaling: TC enhanced phosphorylation of AMPK and CREB and increased BDNF expression; selective AMPK and CREB inhibitors abolished TC neuroprotection. TC failed to alter Akt or ERK activity (two canonical CB2R pathways). Effects were reversed by CB2 antagonist AM630 but not CB1 antagonist AM251. Rat cortical neuron/glia OGD/R model, CB2 knockout validation with AM630/AM251, Western blot, selective kinase inhibitors, in vivo rat ischemia model The American journal of pathology High 23414569
2013 CB2 receptor activation by selective agonist O-1966 decreased nuclear NF-κB and NFAT levels in wild-type T-cells but not in CB2 knockout T-cells, and increased IL-10 production and regulatory T-cell (Treg) percentage in mixed lymphocyte reactions; increased IL-10 partially mediated the immunosuppressive effects. CB2 knockout mouse T-cells, mixed lymphocyte reaction, nuclear transcription factor assays, PCR T-cell activation array, IL-10 ELISA, anti-IL-10 neutralization Journal of neuroimmune pharmacology High 25980325
2013 CB2 receptor modulates axon guidance in the retino-thalamic pathway in a PKA-dependent manner requiring the netrin-1 receptor DCC (Deleted in Colorectal Cancer); CB2R activation induced growth cone morphological changes, and cnr2-/- mice showed abnormal eye-specific segregation of retinal projections in the dLGN. cnr2 knockout mice, in vitro axon guidance assays, PKA inhibitor experiments, in vivo retino-thalamic tracing PloS one High 23951024
2014 GPR55 and CB2 receptors form heteromers in HEK293 cells (confirmed by co-immunoprecipitation and BRET); heteromerization selectively modulates signaling: GPR55-mediated transcription factor activation (NFAT, NF-κB, CRE) was reduced, while ERK1/2-MAPK activation was potentiated in the presence of CB2; CB2 signaling was also modified by co-expression with GPR55. Co-immunoprecipitation, BRET, label-free assays (Epic DMR and CellKey impedance), ERK1/2 phosphorylation assay, gene reporter assays British journal of pharmacology High 25048571
2014 CB2 and GPR55 form heteromers in cancer cells with unique signaling properties; these heteromeric complexes modulate the antitumoral activity of cannabinoids in vivo. Co-immunoprecipitation, proximity ligation assay, signaling assays, in vivo tumor model The Journal of biological chemistry Medium 24942731
2015 HER2 upregulates CB2 expression by activating transcription factor ELK1 via the ERK cascade; increased CB2 expression activates HER2 pro-oncogenic signaling at the level of tyrosine kinase c-SRC; HER2 and CB2 form heteromers in cancer cells. siRNA/shRNA knockdown, overexpression plasmids, co-immunoprecipitation, proximity ligation assay, colocalization, MMTV-neu transgenic mice with CB2 knockout, biochemical signaling assays Journal of the National Cancer Institute High 25855725
2016 CB2 receptor ligands display strong and varied functional selectivity: classic cannabinoids (e.g., JWH133) are highly efficacious for Gi-mediated adenylyl cyclase inhibition but fail to recruit arrestins (G-protein biased); endocannabinoids are also G-protein biased; aminoalkylindoles (e.g., WIN55212-2, UR144) show arrestin recruitment with varying cyclase efficacy; SR144258 is inverse agonist at both pathways; AM630 and JTE907 are inverse agonists at cyclase but low-efficacy agonists for arrestin recruitment. Adenylyl cyclase inhibition assay, β-arrestin recruitment assay (BRET-based), diverse CB2 ligand panel The Journal of pharmacology and experimental therapeutics High 27194477
2018 CXCR4 and CB2 form heterodimers upon simultaneous agonist stimulation; this heterodimeric association inhibits CXCR4-mediated cell migration, invasion, and adhesion through inhibition of the Gα13/RhoA signaling axis, decreasing protein expression of Gα13 and RhoA, abrogating RhoA-mediated cytoskeletal rearrangement, and reducing integrin α5 (ITGA5) expression. Co-immunoprecipitation, confocal colocalization, migration/invasion/adhesion assays, Western blot for Gα13/RhoA, cytoskeletal rearrangement imaging Molecular cancer research : MCR Medium 29330286
2019 Crystal structure of human CB2 receptor in complex with antagonist AM10257 was solved at 2.8 Å resolution. The structure revealed a distinctly different binding pose compared with CB1, but the extracellular portion shares conformational similarity with agonist-bound CB1. Mutagenesis and molecular docking identified molecular determinants of CB2/CB1 selectivity and the CB2 activation mechanism. X-ray crystallography (2.8 Å), site-directed mutagenesis, molecular docking, pharmacological assays Cell High 30639103
2022 CNR2 (CB2 receptor) binds to JAK1 in T cells and inhibits downstream STAT signaling; this was demonstrated using a knock-in mouse model expressing FLAG-tagged Cnr2, with cannabinoids (THC and AEA) impairing tumor-specific T-cell function through CNR2-mediated JAK1/STAT inhibition. FLAG-Cnr2 knock-in mouse model, co-immunoprecipitation (FLAG pulldown for JAK1 binding), T-cell functional assays, STAT phosphorylation assays, in vivo tumor models Signal transduction and targeted therapy High 35383142
2022 CB2 receptors localized to peripheral sensory neurons (advillin-expressing) are necessary for both CB2 agonist (AM1710 and LY2828360) antinociceptive efficacy and sparing of morphine tolerance in a mouse model of antiretroviral toxic neuropathy; advillinCre/+;CB2f/f conditional knockout mice lacked these CB2 agonist effects. Conditional knockout (advillinCre/+;CB2f/f), global CB2 KO, neuropathic pain behavioral assays, morphine tolerance assay, cytokine mRNA measurement Pharmacological research High 36417942
2022 CB2 receptor activation inhibits microglial phagocytic function through β-arrestin2/ERK1/2 and PI3K/AKT/GSK-3β signaling pathways leading to nuclear translocation of Nurr1; positive feedback exists between CB2 receptor and Nurr1 expression; ERK1/2 plays a more dominant role than AKT in the CB2-Nurr1 axis. BV-2 cells and primary microglia, CB2 agonists (JWH015, 2-AG), selective pathway inhibitors (U0126, LY294002), Nurr1 overexpression, nuclear fractionation Western blot, phagocytosis assay Acta pharmacologica Sinica Medium 35132190
2023 Cryo-EM structures of CB2 receptor bound to multiple agonists (LEI-102, APD371, HU308, CP55,940) identified key residues for CB2 activation by site-directed mutagenesis and binding kinetics; highly lipophilic agonists (HU308 and endocannabinoids) access the binding pocket through a membrane channel formed by TM1-TM7, while more polar agonists enter directly. Cryo-EM structural determination, site-directed mutagenesis, radioligand binding kinetics, molecular docking, in vivo pharmacology (oral efficacy in nephropathy model) Nature communications High 36922494
2024 A homobivalent ligand simultaneously binding both protomers of the CB2 receptor homodimer (one pharmacophore at orthosteric site, one at a TM1-TM7 membrane-oriented pocket of partner protomer) modulates CB2R homodimerization dynamics, resulting in increased potency for Gi-mediated signaling and enhanced β-arrestin recruitment. Computational docking, BRET for homodimerization, Gi signaling assays, β-arrestin recruitment assays, bivalent ligand pharmacology Pharmacological research Medium 39179054

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacology & therapeutics 1199 9336020
2010 CB2: a cannabinoid receptor with an identity crisis. British journal of pharmacology 501 20590558
2016 The CB2 receptor and its role as a regulator of inflammation. Cellular and molecular life sciences : CMLS 452 27402121
2006 Peripheral cannabinoid receptor, CB2, regulates bone mass. Proceedings of the National Academy of Sciences of the United States of America 428 16407142
2006 Discovery of the presence and functional expression of cannabinoid CB2 receptors in brain. Annals of the New York Academy of Sciences 425 17105950
2008 Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures--a short review. Pharmacology, biochemistry, and behavior 332 18584858
2009 Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation. Expert reviews in molecular medicine 328 19152719
2019 Crystal Structure of the Human Cannabinoid Receptor CB2. Cell 307 30639103
2006 Cannabinoid CB2 receptor: a new target for controlling neural cell survival? Trends in pharmacological sciences 306 17141334
2017 CB1 and CB2 Receptor Pharmacology. Advances in pharmacology (San Diego, Calif.) 262 28826534
2014 CB2 Cannabinoid receptors as a therapeutic target-what does the future hold? Molecular pharmacology 213 25106425
2009 Species differences in cannabinoid receptor 2 (CNR2 gene): identification of novel human and rodent CB2 isoforms, differential tissue expression and regulation by cannabinoid receptor ligands. Genes, brain, and behavior 208 19496827
2012 Cannabinoid receptors CB1 and CB2 form functional heteromers in brain. The Journal of biological chemistry 192 22532560
2017 Cannabinoid CB1 and CB2 Receptor Signaling and Bias. Cannabis and cannabinoid research 171 28861504
2019 Progress in brain cannabinoid CB2 receptor research: From genes to behavior. Neuroscience and biobehavioral reviews 166 30611802
2005 Expression of the cannabinoid CB2 receptor in the rat cerebellum: an immunohistochemical study. Neuroscience letters 166 16356641
2008 Targeting CB2 receptors and the endocannabinoid system for the treatment of pain. Brain research reviews 162 19150370
2012 CB2 receptor and amyloid pathology in frontal cortex of Alzheimer's disease patients. Neurobiology of aging 157 22763024
2002 Cloning and molecular characterization of the rat CB2 cannabinoid receptor. Biochimica et biophysica acta 149 12084572
2011 Unraveling the complexities of cannabinoid receptor 2 (CB2) immune regulation in health and disease. Immunologic research 148 21626285
2006 CB2 cannabinoid receptor mediation of antinociception. Pain 146 16563625
2009 Brain cannabinoid CB2 receptor in schizophrenia. Biological psychiatry 144 19931854
2011 CNS effects of CB2 cannabinoid receptors: beyond neuro-immuno-cannabinoid activity. Journal of psychopharmacology (Oxford, England) 141 21447538
1998 Modulation and functional involvement of CB2 peripheral cannabinoid receptors during B-cell differentiation. Blood 141 9808554
2013 Activation of cannabinoid CB2 receptor-mediated AMPK/CREB pathway reduces cerebral ischemic injury. The American journal of pathology 135 23414569
2020 CB2 Receptor in Microglia: The Guardian of Self-Control. International journal of molecular sciences 120 33375006
2015 Neuronal expression of CB2 cannabinoid receptor mRNAs in the mouse hippocampus. Neuroscience 118 26515747
2007 CB2 cannabinoid receptors promote mouse neural stem cell proliferation. The European journal of neuroscience 116 17328768
2000 Expression of CB2 cannabinoid receptor mRNA in adult rat retina. Visual neuroscience 115 10750830
2009 The endocannabinoid system and pivotal role of the CB2 receptor in mouse spermatogenesis. Proceedings of the National Academy of Sciences of the United States of America 114 19541620
2013 Therapeutic utility of cannabinoid receptor type 2 (CB(2)) selective agonists. Journal of medicinal chemistry 109 23865723
2007 The role of the cannabinoid CB2 receptor in pain transmission and therapeutic potential of small molecule CB2 receptor agonists. Current medicinal chemistry 109 17430144
2014 Heteromerization of GPR55 and cannabinoid CB2 receptors modulates signalling. British journal of pharmacology 107 25048571
2009 The cannabinoid receptor CB2 exerts antifibrotic effects in experimental dermal fibrosis. Arthritis and rheumatism 105 19333940
2016 CB2 Cannabinoid Receptor As Potential Target against Alzheimer's Disease. Frontiers in neuroscience 103 27303261
2015 Role of cannabinoid receptor CB2 in HER2 pro-oncogenic signaling in breast cancer. Journal of the National Cancer Institute 100 25855725
2014 Targeting CB2-GPR55 receptor heteromers modulates cancer cell signaling. The Journal of biological chemistry 99 24942731
2007 Biology and therapeutic potential of cannabinoid CB2 receptor inverse agonists. British journal of pharmacology 97 17906679
2008 Role of CB2 receptors in neuroprotective effects of cannabinoids. Molecular and cellular endocrinology 96 18291574
2007 CB2 receptors as new therapeutic targets for liver diseases. British journal of pharmacology 91 17952109
2014 What we know and do not know about the cannabinoid receptor 2 (CB2). Seminars in immunology 88 24877594
2019 Cannabichromene is a cannabinoid CB2 receptor agonist. British journal of pharmacology 83 31368508
2005 CB2 receptor ligands. Mini reviews in medicinal chemistry 83 16026310
2024 Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling. Pharmacological research 78 39179054
2016 Functional Selectivity of CB2 Cannabinoid Receptor Ligands at a Canonical and Noncanonical Pathway. The Journal of pharmacology and experimental therapeutics 78 27194477
2019 Cannabinoid CB1 and CB2 Receptor-Mediated Arrestin Translocation: Species, Subtype, and Agonist-Dependence. Frontiers in pharmacology 77 31024316
2008 Cannabinoid CB1 and CB2 receptor ligand specificity and the development of CB2-selective agonists. Current medicinal chemistry 74 18537620
2010 Cannabinoid CB(2) receptors in health and disease. Current medicinal chemistry 73 20166925
2010 CB1 and CB2 cannabinoid receptor expression during development and in epileptogenic developmental pathologies. Neuroscience 72 20621164
2013 Role of cannabinoid CB2 receptor in the reinforcing actions of ethanol. Addiction biology 71 23855434
2010 Brain CB₂ Receptors: Implications for Neuropsychiatric Disorders. Pharmaceuticals (Basel, Switzerland) 71 27713365
2011 CB2 cannabinoid receptor targets mitogenic Gi protein-cyclin D1 axis in osteoblasts. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 69 20803555
2007 Endocannabinoid receptor CB2 in nonalcoholic fatty liver disease. Liver international : official journal of the International Association for the Study of the Liver 65 17311616
2000 The search for selective ligands for the CB2 receptor. Current pharmaceutical design 64 10903395
2022 Cannabis suppresses antitumor immunity by inhibiting JAK/STAT signaling in T cells through CNR2. Signal transduction and targeted therapy 62 35383142
2016 Cannabinoid receptor 2 (CB2) agonists and antagonists: a patent update. Expert opinion on therapeutic patents 61 27215781
2014 Cannabinoids in pain management: CB1, CB2 and non-classic receptor ligands. Expert opinion on investigational drugs 60 24836296
2005 Targeting the cannabinoid CB2 receptor: mutations, modeling and development of CB2 selective ligands. Current medicinal chemistry 59 15892633
2023 Structural basis of selective cannabinoid CB2 receptor activation. Nature communications 58 36922494
2011 CB₂: therapeutic target-in-waiting. Progress in neuro-psychopharmacology & biological psychiatry 58 22197668
2006 Targeting the CB2 receptor for immune modulation. Expert opinion on therapeutic targets 58 16981823
2009 Predominant CB2 receptor expression in endothelial cells of glioblastoma in humans. Brain research bulletin 56 19480992
2022 New Insights and Potential Therapeutic Targeting of CB2 Cannabinoid Receptors in CNS Disorders. International journal of molecular sciences 54 35055161
2013 Cannabinoid receptor CB2 modulates axon guidance. PloS one 54 23951024
2015 Expression Analysis of CB2-GFP BAC Transgenic Mice. PloS one 53 26406232
2008 Functional and immunohistochemical characterization of CB1 and CB2 receptors in rat bladder. Urology 53 18468662
2007 Targeting the cannabinoid CB2 receptor: modelling and structural determinants of CB2 selective ligands. British journal of pharmacology 53 17982473
2012 CB1 and CB2 receptor expression and promoter methylation in patients with cannabis dependence. European addiction research 47 22948261
2023 CB2 receptor in the CNS: From immune and neuronal modulation to behavior. Neuroscience and biobehavioral reviews 46 37164044
2022 Expression and Functions of the CB2 Receptor in Human Leukocytes. Frontiers in pharmacology 46 35273503
2022 Developing the Cannabinoid Receptor 2 (CB2) pharmacopoeia: past, present, and future. Trends in pharmacological sciences 46 35906103
2015 A CB2-Selective Cannabinoid Suppresses T-Cell Activities and Increases Tregs and IL-10. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 46 25980325
2010 Immunoregulation of a CB2 receptor agonist in a murine model of neuroAIDS. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 46 20549374
2008 Cannabinoid CB2 receptor expression in the rat brainstem cochlear and vestibular nuclei. Acta oto-laryngologica 45 19086305
2018 Agonist-induced CXCR4 and CB2 Heterodimerization Inhibits Gα13/RhoA-mediated Migration. Molecular cancer research : MCR 44 29330286
2018 Emerging strategies targeting CB2 cannabinoid receptor: Biased agonism and allosterism. Biochemical pharmacology 44 30055149
2011 Genetic association between bipolar disorder and 524A>C (Leu133Ile) polymorphism of CNR2 gene, encoding for CB2 cannabinoid receptor. Journal of affective disorders 43 21658778
2011 CNR2 functional variant (Q63R) influences childhood immune thrombocytopenic purpura. Haematologica 43 21828121
2019 Cannabidiol inhibits sucrose self-administration by CB1 and CB2 receptor mechanisms in rodents. Addiction biology 41 31215752
2007 CB2 receptors in reproduction. British journal of pharmacology 40 17828289
2024 The Impact of the CB2 Cannabinoid Receptor in Inflammatory Diseases: An Update. Molecules (Basel, Switzerland) 39 39064959
2017 Combined deficiency of the Cnr1 and Cnr2 receptors protects against age-related bone loss by osteoclast inhibition. Aging cell 36 28752643
2017 Cannabinoids Modulate Neuronal Activity and Cancer by CB1 and CB2 Receptor-Independent Mechanisms. Frontiers in pharmacology 36 29066974
2022 Effects of CB2 Receptor Modulation on Macrophage Polarization in Pediatric Celiac Disease. Biomedicines 35 35453624
2009 The cannabinoid receptor type 2 (CNR2) gene is associated with hand bone strength phenotypes in an ethnically homogeneous family sample. Human genetics 34 19565271
2019 HTR1D, TIMP1, SERPINE1, MMP3 and CNR2 affect the survival of patients with colon adenocarcinoma. Oncology letters 32 31452735
2016 The central cannabinoid receptor type-2 (CB2) and chronic pain. The International journal of neuroscience 32 27842450
2022 A peripheral CB2 cannabinoid receptor mechanism suppresses chemotherapy-induced peripheral neuropathy: evidence from a CB2 reporter mouse. Pain 31 35001054
2022 Cannabinoid CB2 Receptors in Neurodegenerative Proteinopathies: New Insights and Therapeutic Potential. Biomedicines 31 36551756
2019 Allosteric modulators targeting cannabinoid cb1 and cb2 receptors: implications for drug discovery. Future medicinal chemistry 31 31517528
2002 Expression of CB2 cannabinoid receptor in Pichia pastoris. Protein expression and purification 31 12460775
2022 Peripheral sensory neuron CB2 cannabinoid receptors are necessary for both CB2-mediated antinociceptive efficacy and sparing of morphine tolerance in a mouse model of anti-retroviral toxic neuropathy. Pharmacological research 30 36417942
2021 Cannabinoid receptor CB2 ablation protects against TAU induced neurodegeneration. Acta neuropathologica communications 30 34001284
2006 Bacterial expression of functional, biotinylated peripheral cannabinoid receptor CB2. Protein expression and purification 30 16621595
2022 CB2 receptor activation inhibits the phagocytic function of microglia through activating ERK/AKT-Nurr1 signal pathways. Acta pharmacologica Sinica 29 35132190
2018 Pharmacological regulation of cannabinoid CB2 receptor modulates the reinforcing and motivational actions of ethanol. Biochemical pharmacology 29 30063884
2023 Microglial Cannabinoid CB2 Receptors in Pain Modulation. International journal of molecular sciences 28 36768668
2022 Immunomodulatory Role of CB2 Receptors in Emotional and Cognitive Disorders. Frontiers in psychiatry 27 35492718
2019 The association of endocannabinoid receptor genes (CNR1 and CNR2) polymorphisms with depression: A meta-analysis. Medicine 27 31725603
2012 Cannabinoid receptor CB2 protects against balloon-induced neointima formation. American journal of physiology. Heart and circulatory physiology 27 22227125

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