Affinage

CNR2

Cannabinoid receptor 2 · UniProt P34972

Round 2 corrected
Length
360 aa
Mass
39.7 kDa
Annotated
2026-04-28
130 papers in source corpus 50 papers cited in narrative 51 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CNR2 (CB2) is a Gi/o-protein-coupled cannabinoid receptor predominantly expressed in immune cells (B cells, macrophages, microglia) and peripheral tissues—with regulated expression also in CNS neurons—that transduces endocannabinoid and phytocannabinoid signals into anti-inflammatory, immunomodulatory, and metabolic outcomes (PMID:7689702, PMID:7556170, PMID:26833913). Upon agonist binding, CB2 inhibits adenylyl cyclase, activates ERK1/2-MAPK, PI3K/Akt/mTORC1, AMPK/CREB, and Rap1 pathways, recruits β-arrestin, and—from endolysosomal compartments—couples to Gq to mobilize intracellular Ca²⁺, while negatively regulating NF-κB, RhoA, NLRP3 inflammasome, and JAK1-STAT signaling (PMID:8679694, PMID:22102284, PMID:25033246, PMID:19596672, PMID:28782714, PMID:35383142). CB2 forms functionally distinct heteromers with CB1, GPR55, CXCR4, and HER2 that remodel downstream signaling selectivity, and its structural basis—including orthosteric and lipophilicity-gated membrane-channel agonist entry routes—has been defined by crystal and cryo-EM structures (PMID:22532560, PMID:25048571, PMID:30639103, PMID:36922494). Genetic loss of CB2 in mice results in accelerated bone loss, exacerbated hepatic fibrosis, enhanced neuroinflammation, and altered pain sensitivity, establishing CB2 as a physiological brake on inflammation, bone resorption, and nociceptive signaling (PMID:16407142, PMID:15765409, PMID:18334483, PMID:36417942).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1993 High

    Cloning of CNR2 from spleen macrophages established the existence of a second cannabinoid receptor expressed in the periphery and molecularly distinct from the CNS-expressed CB1, resolving whether a single receptor mediated all cannabinoid effects.

    Evidence Molecular cloning from macrophage cDNA, radioligand binding in heterologous cells

    PMID:7689702

    Open questions at the time
    • Post-translational modifications uncharacterized
    • No structural information
    • CNS expression not assessed beyond Northern blot
  2. 1996 High

    Demonstration that CB2 inhibits forskolin-stimulated cAMP production via Gi coupling in transfected cells identified the primary effector mechanism and confirmed functional conservation across species.

    Evidence cAMP assays in CHO cells stably expressing human or mouse CB2

    PMID:8679694

    Open questions at the time
    • Downstream signaling beyond adenylyl cyclase unknown
    • No information on G-protein subtype specificity
    • No endogenous cell system tested
  3. 1998 High

    Mapping of CB2 expression to B-cell subsets and demonstration that CB2 agonism enhances CD40-driven B-cell proliferation provided the first functional link between CB2 signaling and adaptive immune cell biology.

    Evidence Confocal microscopy, flow cytometry, proliferation assays with CB2 antagonist reversal in tonsillar B cells

    PMID:9808554

    Open questions at the time
    • Signaling intermediates between CB2 and proliferative machinery undefined
    • No in vivo B-cell functional data
  4. 2002 Medium

    Cloning of rat CB2 and demonstration that it activates ERK1/2-MAPK expanded the known CB2 effector repertoire beyond adenylyl cyclase inhibition, suggesting mitogenic signaling capacity.

    Evidence Stable CHO cell expression, MAPK phosphorylation assay

    PMID:12084572

    Open questions at the time
    • Pathway intermediates between Gi and ERK not mapped
    • Relevance to endogenous immune cells not tested
  5. 2003 High

    CB2 was shown to mediate microglial migration, suppress Aβ-induced microglial neurotoxicity, and become upregulated on microglia in Alzheimer's disease brain, overturning the view that CB2 is absent from the CNS and identifying it as a neuroinflammatory regulator.

    Evidence Primary microglia migration assays, cortical co-cultures with selective CB2 agonist JWH-133, immunohistochemistry on postmortem AD brain

    PMID:12921861 PMID:14657172 PMID:15728830

    Open questions at the time
    • Whether microglial CB2 is neuroprotective or disease-promoting in vivo remained unclear
    • Mechanism of CB2 transcriptional upregulation in neuroinflammation unknown
  6. 2005 High

    CB2-knockout mice developed exacerbated hepatic fibrosis after toxic injury, and CB2 activation triggered apoptosis of hepatic myofibroblasts, establishing CB2 as a physiological antifibrogenic brake in liver.

    Evidence CB2−/− mice with CCl4 fibrosis model, immunohistochemistry on human cirrhotic liver, ROS and COX-2 assays

    PMID:15765409

    Open questions at the time
    • Downstream transcriptional program of CB2 in stellate cells not defined
    • Whether CB2 agonists can reverse established fibrosis not tested
  7. 2006 High

    Demonstration that CB2-knockout mice exhibit accelerated age-related bone loss and that CB2 agonism inhibits osteoclast precursor proliferation and RANKL expression revealed CB2 as essential for bone mass homeostasis.

    Evidence CB2−/− mice, histomorphometry, ovariectomy rescue with CB2 agonist, bone marrow colony assays

    PMID:16407142

    Open questions at the time
    • Signaling intermediates in osteoclast precursors not mapped
    • Human genetic association with osteoporosis not established
  8. 2007 High

    CB2 activation suppressed TNF-α-induced NF-κB, ICAM-1/VCAM-1, and monocyte transendothelial migration in coronary endothelial cells, and protected against hepatic ischemia/reperfusion injury in vivo, mechanistically linking CB2 to vascular inflammatory control.

    Evidence Human coronary artery endothelial cells, NF-κB reporter, CB2−/− I/R model, cytokine ELISAs

    PMID:17327359 PMID:17660390

    Open questions at the time
    • Direct CB2 signaling events linking Gi to NF-κB suppression not fully resolved
    • Receptor desensitization kinetics in endothelium unknown
  9. 2008 High

    Detection of CB2 mRNA and protein on VTA dopamine neurons by electron microscopy, and demonstration that CB2 deficiency worsens autoimmune encephalomyelitis via enhanced myeloid progenitor trafficking, established CB2 function in both the CNS and in autoimmune cell migration control.

    Evidence Transmission EM in rodent brain, CB2−/− EAE model, bone marrow transfer, chemokine profiling

    PMID:18286196 PMID:18334483

    Open questions at the time
    • Electrophysiological consequence of neuronal CB2 not yet shown at single-cell level
    • Mechanism of CB2-dependent chemokine regulation not mapped
  10. 2009 High

    CB2 was found to activate Rap1 in macrophages to suppress CB1-stimulated ROS and proinflammatory mediators, providing a molecular mechanism for CB2's anti-inflammatory role via small GTPase cross-talk; separately, GPR55–CB2 physical interaction was demonstrated to modulate neutrophil migration and degranulation through Rac2/Cdc42.

    Evidence Rap1 pull-down with dominant-negative constructs in macrophages; BRET and co-IP for GPR55–CB2 in neutrophils/HL60 cells

    PMID:19596672 PMID:21467997

    Open questions at the time
    • Whether Rap1 axis operates in non-macrophage contexts unknown
    • GPR55–CB2 heteromer stoichiometry and structural basis undefined
  11. 2011 High

    CB2 was shown to activate PI3K/Akt/mTORC1 to promote neural progenitor proliferation and Gi–ERK1/2–MAPKAPK2–CREB–cyclin D1 for osteoblast mitogenesis, mapping cell-type-specific signaling cascades downstream of CB2; CB1–CB2 heteromers were identified in brain with bidirectional cross-antagonism on Akt and neurite outgrowth.

    Evidence CB2−/− neural progenitors, PI3K/Akt inhibitors, siRNA of MAPKAPK2, BRET/FRET/co-IP in neuronal cells and rat brain

    PMID:20803555 PMID:22102284 PMID:22532560

    Open questions at the time
    • Heteromer stoichiometry not determined
    • In vivo consequence of CB1–CB2 heteromerization on behavior unknown
    • Whether mTORC1 axis contributes to tumor biology not tested
  12. 2014 High

    Discovery that CB2 localizes to endolysosomes and, upon intracellular agonist delivery, couples to Gq to release Ca²⁺ from IP3-sensitive and acidic stores demonstrated a previously unrecognized compartment-dependent signaling mode distinct from canonical plasma membrane Gi signaling.

    Evidence Microinjection of agonists into CB2-expressing U2OS cells, Ca²⁺ imaging, Gq inhibitors, endolysosomal markers

    PMID:25033246

    Open questions at the time
    • Physiological ligand delivery route to endolysosomal CB2 unclear
    • Whether endolysosomal CB2 signaling occurs in immune cells not tested
    • Structural basis for Gq coupling not resolved
  13. 2015 High

    HER2 was found to transcriptionally upregulate CB2 via ELK1–ERK and to form HER2–CB2 heteromers that activate c-SRC pro-oncogenic signaling; CB2 genetic inactivation impaired HER2-driven mammary tumorigenesis, revealing CB2 as a co-opted oncogenic effector in breast cancer.

    Evidence siRNA/shRNA, co-IP, PLA, ELK1 reporter, MMTV-neu CB2−/− mouse model, human tumor tissue arrays

    PMID:25855725

    Open questions at the time
    • Whether HER2–CB2 heteromer is druggable unknown
    • Downstream transcriptional program of CB2–c-SRC not mapped
  14. 2016 High

    Electrophysiological recording from single dissociated VTA DA neurons confirmed functional CB2 receptors inhibit neuronal firing, and intra-accumbal CB2 agonism reduced cocaine-enhanced dopamine and self-administration, establishing a direct neuronal function for CB2 in reward circuitry.

    Evidence Single-cell electrophysiology, in vivo microdialysis, intra-NAcc microinjection with CB2 antagonist reversal

    PMID:26833913

    Open questions at the time
    • Postsynaptic vs presynaptic CB2 mechanism in DA neurons not resolved
    • Whether CB2 modulates other addictive substances through same circuit not tested
  15. 2017 High

    CB2 was identified as a central effector of the PAX5/IKZF1 metabolic gatekeeper program in B-lymphoid cells, where it restricts glucose and energy supply; pharmacological CB2 agonism synergized with glucocorticoids to induce metabolic crisis in pre-B ALL, redefining CB2 as a metabolic checkpoint.

    Evidence CRISPR/Cas9 screen, ChIP-seq, RNA-seq, metabolic flux analysis, pre-B ALL mouse model

    PMID:28792788

    Open questions at the time
    • Metabolic effectors downstream of CB2 (glucose transporter regulation) not fully mapped
    • Whether this mechanism operates outside B-lymphoid lineage unknown
  16. 2019 High

    The 2.8 Å crystal structure of CB2 bound to antagonist AM10257 revealed a ligand-binding pose distinct from CB1 and explained divergent functional selectivity between the two receptors, providing the first atomic-resolution template for CB2 drug design.

    Evidence X-ray crystallography, site-directed mutagenesis, molecular docking, functional pharmacology

    PMID:30639103

    Open questions at the time
    • Active-state structure not yet available at this point
    • Mechanism of agonist-induced conformational change not resolved
  17. 2022 High

    CNR2 was found to physically bind JAK1 and suppress JAK-STAT signaling in T cells, with THC and anandamide impairing tumor-specific T cell responses through this axis, uncovering a non-canonical CB2 signaling mechanism relevant to tumor immune evasion.

    Evidence FLAG-Cnr2 knock-in mouse, endogenous co-IP of CNR2–JAK1, STAT phosphorylation, tumor-specific T cell functional assays

    PMID:35383142

    Open questions at the time
    • Structural basis of CNR2–JAK1 interaction unknown
    • Whether JAK1 inhibition is Gi-dependent or independent not resolved
    • Relevance to non-tumor immunity untested
  18. 2022 High

    Conditional deletion of CB2 from peripheral sensory neurons (advillin+ cells) abolished CB2 agonist antinociception and morphine tolerance sparing, pinpointing the cell type and anatomical site responsible for CB2-mediated pain modulation.

    Evidence advillinCre/+;CB2f/f conditional knockout, mechanical and cold allodynia, morphine tolerance protocol

    PMID:36417942

    Open questions at the time
    • Signaling pathway in sensory neurons mediating antinociception not defined
    • Whether central CB2 also contributes to pain behavior not addressed
  19. 2023 High

    Cryo-EM structures of CB2 with four selective agonists revealed that lipophilic agonists access the binding pocket through a membrane channel between TM1 and TM7, while polar agonists enter from the extracellular face, explaining ligand-dependent pharmacological differences and enabling rational design of pathway-selective agonists.

    Evidence Cryo-EM structural determination, binding kinetics, site-directed mutagenesis, molecular modeling

    PMID:36922494

    Open questions at the time
    • Structures of CB2 heteromers not available
    • Whether membrane-channel entry route is physiologically utilized by endocannabinoids requires validation
    • No structure of CB2 in complex with Gq

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of CB2 heteromers (CB1, GPR55, HER2, CXCR4), the mechanism by which endolysosomal CB2 switches from Gi to Gq coupling, the full signaling cascade linking CB2 to JAK1 inhibition, and whether CB2's metabolic gatekeeper role in B-lymphoid cells extends to other immune lineages.
  • No heteromer structures available
  • Endolysosomal Gq coupling mechanism unresolved
  • CNR2–JAK1 structural interface undefined
  • Metabolic checkpoint function outside B-lineage untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005764 lysosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-168256 Immune System 6 R-HSA-112316 Neuronal System 2 R-HSA-1266738 Developmental Biology 2 R-HSA-1430728 Metabolism 1
Partners
CNR1CXCR4DCCERBB2GPR55JAK1RAP1A
Complex memberships
CB1-CB2 heteromerCB2-CXCR4 heteromerCB2-GPR55 heteromerCB2-HER2 heteromer

Evidence

Reading pass · 51 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 CNR2 (CB2) was cloned from macrophages in the marginal zone of spleen; it encodes a G-protein-coupled receptor for cannabinoids that is expressed in the periphery (macrophages/spleen) but not in the brain, establishing it as the peripheral cannabinoid receptor distinct from the CNS-expressed CB1. Molecular cloning, receptor expression in heterologous cells, radioligand binding Nature High 7689702
1995 CB2 mRNA is expressed at 10–100-fold higher levels in immune tissues than CB1, with rank order B-cells > NK cells >> monocytes > PMNs > T8 > T4 cells; CB2 protein was confirmed by immunohistology restricted to B-lymphocyte-enriched mantle zones of secondary follicles in tonsil. Quantitative RT-PCR, Northern blot, immunohistochemistry on human immune tissues and leukocyte subpopulations European journal of biochemistry High 7556170
1996 Mouse CB2 (mCB2) was cloned from a splenocyte cDNA library; both hCB2 and mCB2 mediate agonist-stimulated inhibition of forskolin-induced cAMP production in stably transfected CHO cells, demonstrating Gi-coupled adenylyl cyclase inhibition as the primary effector mechanism. Molecular cloning, cAMP assay in transfected CHO cells, radioligand binding Biochimica et biophysica acta High 8679694
1997 CB2 is coupled to Gi-proteins; its effector systems include inhibition of adenylyl cyclase and modulation of ion channels; CB2 is present in peripheral tissues and immune cells but absent from the CNS under normal conditions. Pharmacological review integrating binding assays, functional effector studies, and tissue distribution data Pharmacology & therapeutics High 9336020
1998 CB2 receptors are most abundantly expressed in peripheral blood and tonsillar B cells among leukocytes; CB2 expression is downregulated during B-cell differentiation (lowest in germinal-center centroblasts); CD40-mediated activation upregulates CB2 within 24 h; CB2 agonist CP55,940 enhances CD40-mediated B-cell proliferation in a CB2-antagonist-reversible manner. Anti-CB2 immunopurified antibody staining, dual-color confocal microscopy, RT-PCR, Western blot, flow cytometry, proliferation assays with selective antagonist SR144528 Blood High 9808554
1999 HU-308, a CB2-selective agonist (Ki = 22.7 nM at CB2, >10 µM at CB1), inhibits forskolin-stimulated cAMP production in CB2-transfected cells but not CB1-transfected cells, and produces anti-inflammatory and peripheral analgesic effects blocked by CB2 antagonist SR-144528 but not CB1 antagonist SR-141716A, confirming peripheral CB2-mediated signaling. Radioligand binding, cAMP assay in transfected cells, in vivo pharmacology with selective antagonists Proceedings of the National Academy of Sciences High 10588688
2002 Rat CB2 (rCB2) was cloned and found to be 410 amino acids, with a longer C-terminus than human or mouse CB2; rCB2 activates MAP kinase (ERK1/2) when stably expressed in CHO cells, establishing MAPK activation as a CB2 signaling output. cDNA library cloning, CHO cell stable expression, MAPK phosphorylation assay Biochimica et biophysica acta Medium 12084572
2002 CB2 cannabinoid receptor was functionally expressed in Pichia pastoris with retained pharmacological binding profile; purified receptor was confirmed by MALDI/TOF and ESI mass spectrometry, providing the first purified preparation for structural characterization. Heterologous expression in yeast, radioligand binding, metal-chelating chromatography purification, mass spectrometry peptide sequencing Protein expression and purification Medium 12460775
2003 CB2 receptor activation with selective agonist JWH-133 induced growth inhibition of skin tumors in vivo accompanied by increased apoptosis and impaired tumor vascularization (decreased VEGF, placental growth factor, angiopoietin 2 expression) and abrogation of EGF-R function. In vivo tumor model (nude mice), immunohistochemistry, RT-PCR for angiogenic factors, pharmacological manipulation with selective CB2 agonist Journal of Clinical Investigation Medium 12511587
2003 CB2 receptors on microglial cells mediate blockade of β-amyloid-induced microglial activation and neurotoxicity; cannabinoids including the selective CB2 agonist JWH-133 blocked Aβ-induced microglial activation (mitochondrial activity, TNF-α release, cell morphology) and abrogated microglia-mediated neurotoxicity in cortical co-cultures. Primary microglial cultures, rat cortical co-cultures, selective CB2 agonist, TNF-α ELISA, mitochondrial activity assay, intracerebroventricular WIN55,212-2 in rats Journal of Neuroscience High 15728830
2003 Fatty acid amide hydrolase (FAAH) and CB2 receptors are selectively and abundantly expressed in neuritic plaque-associated astrocytes and microglia, respectively, in Alzheimer's disease brain, while CB1 expression remains unchanged, suggesting CB2 upregulation in neuroinflammation. Immunohistochemical analysis with specific polyclonal antibodies on postmortem AD and control brain sections Journal of Neuroscience Medium 14657172
2003 CB2 receptor (but not CB1) mediates ACPA-induced microglial cell migration via Gi/o protein-coupled signaling; this effect is blocked by CB2 antagonists (SR144528, cannabinol) and abn-CBD receptor antagonists, but not by CB1 antagonist SR141716A. BV-2 microglial cell migration assay, pertussis toxin pretreatment, selective receptor antagonists European journal of pharmacology Medium 12921861
2005 CB2 receptors are upregulated in hepatic myofibroblasts/activated stellate cells in cirrhotic liver (absent from normal liver); CB2 activation triggers antifibrogenic effects including growth inhibition (via cyclooxygenase-2) and apoptosis (via oxidative stress); CB2-/- mice develop enhanced liver fibrosis after CCl4 treatment. Immunohistochemistry on human liver biopsies, RT-PCR, GTPγS assays, culture assays with COX-2 inhibitors, ROS measurement, CB2 knockout mouse model Gastroenterology High 15765409
2006 CB2-deficient mice exhibit markedly accelerated age-related trabecular bone loss, increased osteoclast number, and decreased osteoblast precursors; a CB2-specific agonist inhibits proliferation of osteoclast precursors, reduces RANKL expression in bone marrow-derived osteoblasts/stromal cells, and attenuates ovariectomy-induced bone loss, demonstrating CB2 is essential for normal bone mass maintenance. CB2 knockout mice, histomorphometry, bone marrow colony assays, pharmacological treatment with CB2-selective agonist, ovariectomy model Proceedings of the National Academy of Sciences High 16407142
2006 Alkylamides from Echinacea (dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutylamide A1 and dodeca-2E,4E-dienoic acid isobutylamide A2) bind CB2 with Ki ~60 nM (>25-fold selective over CB1) and elevate total intracellular Ca2+ in CB2-positive HL60 cells via CB2, blocked by CB2 antagonist SR144528; they also upregulate constitutive IL-6 in a CB2-dependent manner. Radioligand displacement assay ([3H]CP-55,940), Ca2+ imaging in CB2+ vs CB2- cells, selective antagonist, IL-6 measurement Journal of Biological Chemistry High 16547349
2007 CB2 activation with the selective agonist JWH133 protects against hepatic ischemia/reperfusion injury by decreasing inflammatory cell infiltration, tissue TNF-α, MIP-1α, MIP-2, lipid peroxidation, and ICAM-1 expression; CB2-/- mice develop increased I/R-induced tissue damage, confirming CB2-mediated hepatoprotection. In vivo mouse I/R model, CB2-/- mice, JWH133 pharmacological treatment, cytokine ELISA, lipid peroxidation assay, ICAM-1/VCAM-1 expression, neutrophil adhesion assay FASEB Journal High 17327359
2007 CB2 receptor activation attenuates TNF-α-induced NF-κB and RhoA activation, upregulation of ICAM-1 and VCAM-1, MCP-1 expression, transendothelial monocyte migration, and monocyte-endothelial adhesion in human coronary artery endothelial cells, identifying CB2 as a regulator of endothelial inflammatory signaling. Human coronary artery endothelial cell cultures, Western blot, RT-PCR, NF-κB luciferase reporter, transendothelial migration assay, monocyte adhesion assay, in vivo aorta experiments American Journal of Physiology. Heart and Circulatory Physiology High 17660390
2007 CB2 receptor inverse agonist Sch.414319 downregulates phosphorylation of the monocyte-specific actin-bundling protein L-plastin in human monocytes, suggesting a mechanism for CB2-mediated inhibition of immune cell motility. Biochemical profiling across 45 enzymes and 80 GPCRs/ion channels, protein phosphorylation analysis in human monocytes, in vivo immune cell mobility assay British Journal of Pharmacology Medium 17906679
2008 CB2 receptor activation (JWH133) mediates antinociception in wild-type mice, with significantly reduced effects in CB2-/- mice, while morphine antinociception was unaffected in CB2-/- mice, genetically confirming that AM1241 produces antinociception specifically through CB2 receptors. CB2 knockout mice, thermal nociception assay, pharmacological challenge with selective agonist AM1241 and WIN55,212-2 Pain High 16563625
2009 CB2 receptor is expressed in mouse male germ cells; the selective CB2 agonist JWH133 induces ERK1/2 MAPK phosphorylation in spermatogonia and promotes their progression toward meiosis (increased SCP3-positive cells and meiotic prophase gene expression), with 2-AG acting as the autocrine endocannabinoid signal. Purified germ cell fractions, primary spermatogonia cultures, selective CB2 agonist treatment, ERK1/2 Western blot, BrdU incorporation, meiotic marker immunostaining Proceedings of the National Academy of Sciences High 19541620
2009 CB2 receptor gene (CNR2) has two promoters transcribing distinct isoforms: CB2A (testis/brain-predominant) and CB2B (spleen/peripheral-predominant); mouse CB2A expression in cerebellum is upregulated by the mixed CB receptor agonist WIN55212-2. Genomic mapping, RT-PCR with isoform-specific primers, Northern blot, drug treatment of mice Genes, Brain, and Behavior Medium 19496827
2009 GPR55 and CB2 receptors physically interact in human neutrophils; GPR55 activation augments CB2-mediated migration while inhibiting CB2-mediated degranulation and ROS production; mechanistically, GPR55 and CB2 interfere with each other's signaling at the level of small GTPases Rac2 and Cdc42. Human neutrophils and HL60 cells, co-immunoprecipitation, BRET, migration assays, degranulation assay, ROS production assay, dominant-negative small GTPase constructs Cell Research High 21467997
2009 CB2 receptor mRNA and protein are expressed in rat brain (including ventral midbrain); mice with reduced CB2 function due to the R63 allele of rs2501432 show lower cAMP responses in transfected CHO cells; CB2 antagonist AM630 exacerbates MK-801- or methamphetamine-induced prepulse inhibition deficits in mice. RT-PCR, in situ hybridization, CHO cell functional assay (cAMP), human genetic association, pharmacological behavioral test Biological Psychiatry Medium 19931854
2011 CB2 receptor-selective agonist HU-308 activates the PI3K/Akt/mTORC1 pathway in hippocampal neural progenitor cells, inhibiting p27Kip1 and inducing proliferation; this effect is blocked by CB2 antagonist SR144528, PI3K/Akt/mTORC1 inhibitors, and absent in CB2-deficient mouse neural progenitors. HiB5 NP cell cultures, brain organotypic cultures, CB2-/- mice, Western blot for p-Akt/p-S6/p27, BrdU incorporation, pharmacological inhibitors, CB2-deficient NP cells Journal of Biological Chemistry High 22102284
2011 CB2 receptors promote mouse neural stem/progenitor cell proliferation via phosphoinositide-3-kinase/Akt signaling; selective CB1 and CB2 antagonists block basal neurosphere proliferation suggesting endocannabinoid tone; PI3K inhibitor BML-257 blocks cannabinoid agonist-stimulated proliferation. Neurosphere culture, BrdU incorporation, selective CB1/CB2 agonists and antagonists, PI3K inhibitor European Journal of Neuroscience Medium 17328768
2011 CB2 receptor in osteoblasts activates a Gi protein–Erk1/2–MAPKAPK2–CREB–cyclin D1 mitogenic axis; CB2 agonist-induced osteoblast proliferation is blocked by pertussis toxin, MEK-Erk1/2 inhibitors (PD098059, U0126), and Mapkapk2 siRNA, identifying the signaling sequence for CB2-driven bone formation. MC3T3-E1 and primary calvarial osteoblast cultures, pertussis toxin, selective kinase inhibitors, siRNA knockdown, Western blot, CREB reporter, cyclin D1 RT-PCR Journal of Bone and Mineral Research High 20803555
2011 CB2 and CB1 receptors form functional heteromers in rat brain (pineal gland, nucleus accumbens, globus pallidus) and in transfected neuronal cells; co-activation of both receptors within CB1–CB2 heteromers produces negative cross-talk in Akt phosphorylation and neurite outgrowth; heteromers exhibit bidirectional cross-antagonism where CB1 antagonists block CB2 agonist effects and vice versa. BRET, FRET, co-immunoprecipitation in transfected neuronal cells and rat brain tissue, Akt phosphorylation assay, neurite outgrowth measurement Journal of Biological Chemistry High 22532560
2013 CB2 receptor activation by trans-caryophyllene ameliorates ischemic neuronal injury through AMPK/CREB signaling: TC enhanced phosphorylation of AMPK and CREB and increased BDNF expression; AMPK and CREB inhibitors abolished neuroprotection; TC had no effect on Akt or ERK activity, distinguishing this pathway from canonical CB2 signaling. Rat cortical neuron/glia cultures, OGD/reoxygenation model, Western blot, selective inhibitors of AMPK and CREB, in vivo MCAo model with infarct measurement American Journal of Pathology Medium 23414569
2013 Agonist-induced formation of CB2–GPR55 heteromers in cancer cells produces unique signaling: ERK1/2-MAPK activation is potentiated while GPR55-mediated transcription factor activation (NFAT, NF-κB, CRE) is reduced; CB2 co-expression modifies GPR55 signaling and vice versa; modulation of these heteromers alters antitumoral activity of cannabinoids in vivo. Co-immunoprecipitation, BRET in HEK293 cells, label-free real-time assays (Epic DMR, CellKey impedance), ERK1/2-MAPK phosphorylation, gene reporter assays, in vivo tumor model British Journal of Pharmacology High 25048571
2014 Agonist-induced CB2–GPR55 heteromers in cancer cells exhibit unique signaling properties distinct from either receptor alone; in vivo, modulation of CB2–GPR55 heteromers modifies antitumoral efficacy of cannabinoids. Co-immunoprecipitation, proximity ligation assay, ERK signaling assays, in vivo tumor model, shRNA modulation of CB2 Journal of Biological Chemistry High 24942731
2014 CB2 receptors localize to endolysosomes as well as the plasma membrane; intracellular CB2 activation by microinjected agonists (2-AG, anandamide, WIN55,212-2) triggers fast, transient Ca2+ elevation from inositol 1,4,5-trisphosphate-sensitive and acidic-like Ca2+ stores via Gq coupling, whereas extracellular anandamide is ineffective; plasmalemmal CB2 activation by 2-AG and WIN55,212-2 triggers delayed, Gq-mediated Ca2+ responses. Ca2+ imaging in CB2-expressing U2OS cells, intracellular microinjection, selective CB2 antagonist AM630, Gq inhibitors, endolysosomal markers Biochemistry High 25033246
2015 HER2 upregulates CB2 expression via the transcription factor ELK1 through the ERK cascade; elevated CB2 activates HER2 pro-oncogenic signaling at the level of the tyrosine kinase c-SRC; HER2 and CB2 form heteromers in breast cancer cells; genetic inactivation of CB2 impairs tumor generation and progression in MMTV-neu mice. siRNA/shRNA knockdown, overexpression, co-immunoprecipitation, proximity ligation assay, colocalization, ELK1 reporter, MMTV-neu CB2-/- mouse model, human tumor tissue arrays Journal of the National Cancer Institute High 25855725
2015 CB2 receptor mediates antinociception in a CB2-/- validated model; AM1241 antinociception is absent in CB2-/- mice but morphine antinociception is normal, confirming specificity; CB2 knockout mice exhibited robust ddC-induced neuropathy (replicated in antiretroviral model). CB2 knockout mice, thermal nociception and mechanical allodynia assays, selective CB2 agonists Pain (replicated in 2022 paper PMID:35001054 and earlier PMID:16563625) High 16563625 35001054
2016 Functional CB2 receptors are expressed in VTA dopamine neurons in rats; CB2 agonist JWH133 inhibits VTA DA neuronal firing in single dissociated neurons; local CB2 agonist in nucleus accumbens inhibits cocaine-enhanced extracellular DA and intravenous cocaine self-administration, blocked by CB2 antagonist AM630. In situ hybridization, immunohistochemistry, single-cell electrophysiology, in vivo microdialysis, i.v. cocaine self-administration with intra-NAcc microinjection Addiction Biology High 26833913
2017 B-lymphoid transcription factors PAX5 and IKZF1 transcriptionally repress CNR2 as part of a metabolic gatekeeper program; CNR2 is identified as a central effector restricting glucose and energy supply in B-lymphoid cells; pharmacological CNR2 agonism synergizes with glucocorticoids to induce energy crisis and cell death in pre-B ALL. ChIP-seq, RNA-seq, CRISPR/Cas9 screen of PAX5/IKZF1 transcriptional targets, metabolic analysis, pharmacological CB2 agonism in pre-B ALL mouse model Nature High 28792788
2018 Agonist co-activation of CXCR4 and CB2 induces heterodimer formation on cancer cell membranes, decreasing Gα13 and RhoA protein levels, abrogating RhoA-mediated cytoskeletal rearrangement, reducing integrin α5 (ITGA5) expression, and inhibiting cell migration, invasion, and adhesion to extracellular matrices. Co-immunoprecipitation, Western blot, RhoA activation assay, migration/invasion/adhesion assays, siRNA knockdown in prostate cancer cells Molecular Cancer Research Medium 29330286
2019 Crystal structure of human CB2 in complex with antagonist AM10257 at 2.8 Å resolution; the structure reveals a binding pose distinct from CB1 but extracellular conformation similar to agonist-bound CB1, explaining AM10257's unexpected opposing functional profile (CB2 antagonism vs CB1 agonism); mutagenesis and molecular docking identify molecular basis for CB1/CB2 functional selectivity and provide insight into CB2 activation mechanism. X-ray crystallography at 2.8 Å, site-directed mutagenesis, molecular docking, functional pharmacology Cell High 30639103
2019 Cannabichromene (CBC) is a selective CB2 receptor agonist: it activates CB2 but not CB1 to produce cell hyperpolarization in AtT20 cells, an effect blocked by AM630 and sensitive to pertussis toxin (Gi coupling); CBC induces loss of cell-surface CB2 receptors and receptor desensitization, indicating recruitment of regulatory mechanisms. AtT20 cells stably expressing HA-tagged CB1 or CB2, membrane potential assay, receptor internalization assay, pertussis toxin treatment, selective antagonist AM630 British Journal of Pharmacology High 31368508
2019 Cannabinoids suppress innate immunity to oral pathogens via a CB2/PI3K axis: THC, CBD, and CBN suppress P. gingivalis-induced cytokine production in human innate cells through CB2 and PI3K; CB2-/- mice lack this suppression in an oral infection model in vivo. Human monocyte cultures, siRNA gene silencing, pharmacological PI3K inhibition, CB2-/- mouse oral infection model, ELISA cytokine measurement Frontiers in Immunology Medium 31681262
2022 CNR2 binds to JAK1 and inhibits downstream STAT signaling in T cells; THC and anandamide impair tumor-specific T cell function through CNR2; discovered using a FLAG-tagged Cnr2 knock-in mouse model and co-immunoprecipitation. FLAG-tagged Cnr2 knock-in mouse model, co-immunoprecipitation of CNR2 with JAK1, STAT phosphorylation assay, tumor-specific T cell functional assay, in vivo tumor models Signal Transduction and Targeted Therapy High 35383142
2022 CB2 localized specifically to peripheral sensory neurons (advillin+ cells) mediates both antinociceptive efficacy of CB2 agonists and sparing of morphine tolerance in a ddC-induced neuropathy model; advillinCre/+;CB2f/f conditional knockout mice lack CB2 agonist antinociception and morphine tolerance sparing, while retaining ddC-induced neuropathy and morphine antinociception. Conditional knockout mice (advillinCre/+;CB2f/f), mechanical allodynia and cold allodynia assays, morphine tolerance protocol, proinflammatory cytokine mRNA measurement Pharmacological Research High 36417942
2022 CB2 expressed in epidermal keratinocytes, Langerhans cells, dendritic cells in dermis, and Merkel cells mediates suppression of chemotherapy-induced peripheral neuropathic nociception; Langerhans cells are dynamically increased in epidermis after paclitaxel treatment; intraplantar CB2 agonist AM1710 elevates IL-10 mRNA in lumbar spinal cord. CB2-GFP BAC reporter mice, anti-GFP immunolabeling, co-expression with cell-type markers, intraplantar drug administration, mechanical/cold allodynia assays, spinal cord cytokine mRNA Pain Medium 35001054
2023 Cryo-EM structures of CB2 in complex with selective agonists (LEI-102, APD371, HU308, CP55,940) identify key residues for CB2 activation; highly lipophilic agonists (HU308, endocannabinoids) access the binding pocket via a membrane channel in TM1-TM7, while more polar agonists (LEI-102, APD371, CP55,940) do not, revealing that lipophilicity governs the route of CB2 engagement. Cryo-EM structural determination, binding kinetics, site-directed mutagenesis, molecular modeling, oral efficacy in chemotherapy-induced nephropathy model Nature Communications High 36922494
2024 CB2 receptor forms homodimers; a homobivalent ligand simultaneously occupying the orthosteric site of one CB2 protomer and a membrane-oriented allosteric pocket (between TM1 and TM7) of the partner protomer locks the homodimer, increasing potency of Gi-mediated signaling and enhancing β-arrestin recruitment. Computational docking, pharmacological assays (cAMP/Gi signaling, β-arrestin recruitment), bivalent ligand design with 14-methylene linker Pharmacological Research Medium 39179054
2008 CB2 receptor mRNA and protein are expressed in dopaminergic neurons of the VTA in mice; CB2 receptors are predominantly located on post-synaptic elements in rodent brain as determined by electron microscopy; CB2-Rs are modulated in brain following exposure to stressors and abused drugs. RT-PCR, immunoblotting, immunohistochemistry, transmission electron microscopy, in situ hybridization, hippocampal cultures, antisense oligonucleotide injection PLoS ONE Medium 18286196
2008 CB2 receptor controls myeloid progenitor cell trafficking toward inflamed spinal cord in EAE; CB2-/- mice show exacerbated disease with increased myeloid progenitor recruitment, T-lymphocyte infiltration, and microglial activation; CB2 activation reduces EAE symptoms through modulation of CCL2, CCL3, CCL5 chemokines and CCR1, CCR2 receptors. CB2-/- mouse EAE model, bone marrow transfer, selective CB2 agonist pharmacology, flow cytometry, RT-PCR for chemokines/receptors, histological analysis Journal of Biological Chemistry High 18334483
2009 CB2 receptor activation inhibits macrophage ROS production via Rap1 activation; CB1 promotes pro-inflammatory ROS and p38-MAPK phosphorylation in macrophages, while CB2 activates Rap1 to negatively regulate CB1-stimulated ROS, TNF-α, and MCP-1 production; dominant-negative Rap1 enhanced CB1-dependent ROS. Selective expression of CB1 or CB2 in peritoneal macrophages, flow cytometry for ROS, p38-MAPK Western blot, pull-down assay for Rap1 activation, dominant-negative Rap1 construct Cardiovascular Research High 19596672
2012 CB2 receptor protects against balloon-induced neointima formation; CB2 activation (JWH133) reduces intimal nuclei, smooth muscle cells, macrophages, and proliferating cells; CB2-/- mice develop increased intima formation with elevated macrophage adhesion, migration, and smooth muscle cell proliferation, and elevated CCR1, CCR5, and CCL2 mRNA in CB2-/- macrophages. CB2-/- mice, pharmacological CB2 activation, carotid balloon injury model, bone marrow-derived macrophage adhesion/migration assays, smooth muscle cell proliferation assay, RT-PCR for adhesion molecules and chemokines American Journal of Physiology. Heart and Circulatory Physiology High 22227125
2013 CB2 receptor modulates axon guidance in the retino-thalamic pathway; CB2R-induced growth cone morphological changes are PKA-dependent and require the netrin-1 receptor DCC (Deleted in Colorectal Cancer); cnr2-/- mice exhibit abnormal eye-specific segregation of retinal projections in the dorsal lateral geniculate nucleus. In vitro retinal axon assays, in vivo cnr2-/- mouse model, pharmacological CB2 manipulation, PKA inhibitor, immunofluorescence for DCC PLoS ONE Medium 23951024
2021 CB2 receptor expression is increased in hippocampal neurons bearing accumulated TAU in a TAU-dependent manner; CB2 ablation in mice protects from neurodegeneration induced by hTAUP301L overexpression, as shown by preserved cognitive behavior, synaptic plasticity, and reduced insoluble TAU aggregates; CB2 upregulation is confirmed in postmortem Alzheimer's disease brain samples. AAV-TAU mouse models, CB2-/- genetic knockout, gene expression analysis, immunofluorescence, behavioral tests, synaptic plasticity measurement, Western blot for TAU aggregates, human AD postmortem brain Acta Neuropathologica Communications Medium 34001284
2017 CB2 receptor stimulation (JWH133) inhibits NLRP3 inflammasome activation in inflamed skin macrophages; CB2 knockout mice show attenuated EA effects on NLRP3 inflammasomes; in vitro CB2 stimulation in macrophage cell lines directly inhibits NLRP3 inflammasome activation, defining CB2 as a negative regulator of NLRP3 inflammasome. CFA-induced inflammatory pain rat model, electroacupuncture, CB2-/- mice, caspase-1 activity assay, Western blot, immunofluorescence, in vitro macrophage CB2 stimulation Brain, Behavior, and Immunity Medium 28782714

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Molecular characterization of a peripheral receptor for cannabinoids. Nature 3942 7689702
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
1995 Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. European journal of biochemistry 1352 7556170
1997 Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacology & therapeutics 1197 9336020
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2005 Prevention of Alzheimer's disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. The Journal of neuroscience : the official journal of the Society for Neuroscience 607 15728830
2010 CB2: a cannabinoid receptor with an identity crisis. British journal of pharmacology 497 20590558
2003 Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brains. The Journal of neuroscience : the official journal of the Society for Neuroscience 470 14657172
1999 HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor. Proceedings of the National Academy of Sciences of the United States of America 454 10588688
2016 The CB2 receptor and its role as a regulator of inflammation. Cellular and molecular life sciences : CMLS 439 27402121
2006 Peripheral cannabinoid receptor, CB2, regulates bone mass. Proceedings of the National Academy of Sciences of the United States of America 424 16407142
2006 Discovery of the presence and functional expression of cannabinoid CB2 receptors in brain. Annals of the New York Academy of Sciences 424 17105950
2005 Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology 390 15765409
2001 CB2 cannabinoid receptor-mediated peripheral antinociception. Pain 334 11514083
2009 Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation. Expert reviews in molecular medicine 324 19152719
2003 Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. The Journal of clinical investigation 311 12511587
2006 Cannabinoid CB2 receptor: a new target for controlling neural cell survival? Trends in pharmacological sciences 304 17141334
2019 Crystal Structure of the Human Cannabinoid Receptor CB2. Cell 300 30639103
2004 Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study. Synapse (New York, N.Y.) 258 15266552
2017 CB1 and CB2 Receptor Pharmacology. Advances in pharmacology (San Diego, Calif.) 254 28826534
2007 The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration. Current neuropharmacology 254 18615177
2005 Distribution of cannabinoid receptor 1 (CB1) and 2 (CB2) on sensory nerve fibers and adnexal structures in human skin. Journal of dermatological science 239 15927811
2007 CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion. American journal of physiology. Heart and circulatory physiology 225 17660390
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
2009 CB1 and CB2 cannabinoid receptors differentially regulate the production of reactive oxygen species by macrophages. Cardiovascular research 207 19596672
2007 Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 207 17327359
2008 Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects. PloS one 204 18286196
2017 Metabolic gatekeeper function of B-lymphoid transcription factors. Nature 197 28192788
2012 Cannabinoid receptors CB1 and CB2 form functional heteromers in brain. The Journal of biological chemistry 192 22532560
2006 Alkylamides from Echinacea are a new class of cannabinomimetics. Cannabinoid type 2 receptor-dependent and -independent immunomodulatory effects. The Journal of biological chemistry 186 16547349
2013 Cannabinoid receptor 2: potential role in immunomodulation and neuroinflammation. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 184 23471521
2017 Cannabinoid CB1 and CB2 Receptor Signaling and Bias. Cannabis and cannabinoid research 169 28861504
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2005 Expression of the cannabinoid CB2 receptor in the rat cerebellum: an immunohistochemical study. Neuroscience letters 164 16356641
2008 Targeting CB2 receptors and the endocannabinoid system for the treatment of pain. Brain research reviews 162 19150370
2019 Progress in brain cannabinoid CB2 receptor research: From genes to behavior. Neuroscience and biobehavioral reviews 161 30611802
2015 Potential of the cannabinoid CB(2) receptor as a pharmacological target against inflammation in Parkinson's disease. Progress in neuro-psychopharmacology & biological psychiatry 161 25863279
2011 GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils. Cell research 158 21467997
2007 Presence of functional cannabinoid receptors in human endocrine pancreas. Diabetologia 158 18092149
2005 Cannabinoid receptor type 2 gene is associated with human osteoporosis. Human molecular genetics 157 16204352
2012 CB2 receptor and amyloid pathology in frontal cortex of Alzheimer's disease patients. Neurobiology of aging 154 22763024
2011 Deletion of CB2 cannabinoid receptor induces schizophrenia-related behaviors in mice. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 154 21430651
2002 Presence and regulation of the endocannabinoid system in human dendritic cells. European journal of biochemistry 153 12153574
1996 Molecular cloning, expression and function of the murine CB2 peripheral cannabinoid receptor. Biochimica et biophysica acta 150 8679694
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 147 21626285
2006 CB2 cannabinoid receptor mediation of antinociception. Pain 146 16563625
2008 The CB(2) cannabinoid receptor controls myeloid progenitor trafficking: involvement in the pathogenesis of an animal model of multiple sclerosis. The Journal of biological chemistry 145 18334483
2006 Cannabinoid receptor agonist-induced apoptosis of human prostate cancer cells LNCaP proceeds through sustained activation of ERK1/2 leading to G1 cell cycle arrest. The Journal of biological chemistry 144 17068343
2009 Brain cannabinoid CB2 receptor in schizophrenia. Biological psychiatry 143 19931854
1998 Modulation and functional involvement of CB2 peripheral cannabinoid receptors during B-cell differentiation. Blood 141 9808554
2011 CNS effects of CB2 cannabinoid receptors: beyond neuro-immuno-cannabinoid activity. Journal of psychopharmacology (Oxford, England) 140 21447538
2011 CB2 cannabinoid receptors promote neural progenitor cell proliferation via mTORC1 signaling. The Journal of biological chemistry 137 22102284
2013 Activation of cannabinoid CB2 receptor-mediated AMPK/CREB pathway reduces cerebral ischemic injury. The American journal of pathology 134 23414569
2006 Presence of the cannabinoid receptors, CB1 and CB2, in human omental and subcutaneous adipocytes. Histochemistry and cell biology 130 16395612
2016 Expression of functional cannabinoid CB2 receptor in VTA dopamine neurons in rats. Addiction biology 121 26833913
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
2014 Heteromerization of GPR55 and cannabinoid CB2 receptors modulates signalling. British journal of pharmacology 107 25048571
2013 Therapeutic utility of cannabinoid receptor type 2 (CB(2)) selective agonists. Journal of medicinal chemistry 107 23865723
2009 The cannabinoid receptor CB2 exerts antifibrotic effects in experimental dermal fibrosis. Arthritis and rheumatism 105 19333940
2006 Involvement of cannabinoid CB2 receptor in alcohol preference in mice and alcoholism in humans. The pharmacogenomics journal 104 17189959
2015 Role of cannabinoid receptor CB2 in HER2 pro-oncogenic signaling in breast cancer. Journal of the National Cancer Institute 98 25855725
2014 Targeting CB2-GPR55 receptor heteromers modulates cancer cell signaling. The Journal of biological chemistry 98 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 95 18291574
2003 3D structural model of the G-protein-coupled cannabinoid CB2 receptor. Proteins 93 14517981
2015 Effects of pro-inflammatory cytokines on cannabinoid CB1 and CB2 receptors in immune cells. Acta physiologica (Oxford, England) 92 25704169
2017 Electroacupuncture inhibits NLRP3 inflammasome activation through CB2 receptors in inflammatory pain. Brain, behavior, and immunity 91 28782714
2014 What we know and do not know about the cannabinoid receptor 2 (CB2). Seminars in immunology 88 24877594
2003 Arachidonylcyclopropylamide increases microglial cell migration through cannabinoid CB2 and abnormal-cannabidiol-sensitive receptors. European journal of pharmacology 87 12921861
2004 Species comparison and pharmacological characterization of rat and human CB2 cannabinoid receptors. European journal of pharmacology 86 15556131
2006 Cannabinoid CB2/CB1 selectivity. Receptor modeling and automated docking analysis. Journal of medicinal chemistry 84 16451064
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
2010 The levels of the endocannabinoid receptor CB2 and its ligand 2-arachidonoylglycerol are elevated in endometrial carcinoma. Endocrinology 76 20133454
2002 Inhibition of pain responses by activation of CB(2) cannabinoid receptors. Chemistry and physics of lipids 74 12505700
2010 Cannabinoid CB(2) receptors in health and disease. Current medicinal chemistry 73 20166925
2013 Role of cannabinoid CB2 receptor in the reinforcing actions of ethanol. Addiction biology 70 23855434
2024 Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling. Pharmacological research 69 39179054
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 61 35383142
2019 Marijuana-Derived Cannabinoids Trigger a CB2/PI3K Axis of Suppression of the Innate Response to Oral Pathogens. Frontiers in immunology 60 31681262
2016 Cannabinoid receptor 2 (CB2) agonists and antagonists: a patent update. Expert opinion on therapeutic patents 60 27215781
2014 Cannabinoids in pain management: CB1, CB2 and non-classic receptor ligands. Expert opinion on investigational drugs 59 24836296
2006 Targeting the CB2 receptor for immune modulation. Expert opinion on therapeutic targets 58 16981823
2015 Time-Dependent Protection of CB2 Receptor Agonist in Stroke. PloS one 57 26186541
2011 CB₂: therapeutic target-in-waiting. Progress in neuro-psychopharmacology & biological psychiatry 57 22197668
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
2023 Structural basis of selective cannabinoid CB2 receptor activation. Nature communications 52 36922494
2014 Differential activation of intracellular versus plasmalemmal CB2 cannabinoid receptors. Biochemistry 52 25033246
2008 Functional and immunohistochemical characterization of CB1 and CB2 receptors in rat bladder. Urology 51 18468662
2022 Developing the Cannabinoid Receptor 2 (CB2) pharmacopoeia: past, present, and future. Trends in pharmacological sciences 46 35906103
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
2022 Expression and Functions of the CB2 Receptor in Human Leukocytes. Frontiers in pharmacology 43 35273503
2018 Emerging strategies targeting CB2 cannabinoid receptor: Biased agonism and allosterism. Biochemical pharmacology 43 30055149
2018 Agonist-induced CXCR4 and CB2 Heterodimerization Inhibits Gα13/RhoA-mediated Migration. Molecular cancer research : MCR 42 29330286
2023 CB2 receptor in the CNS: From immune and neuronal modulation to behavior. Neuroscience and biobehavioral reviews 40 37164044
2019 Cannabidiol inhibits sucrose self-administration by CB1 and CB2 receptor mechanisms in rodents. Addiction biology 39 31215752
2024 The Impact of the CB2 Cannabinoid Receptor in Inflammatory Diseases: An Update. Molecules (Basel, Switzerland) 38 39064959
2007 The cannabinoid CB(2) receptor: a good friend in the gut. Neurogastroenterology and motility 38 17727390
2017 Combined deficiency of the Cnr1 and Cnr2 receptors protects against age-related bone loss by osteoclast inhibition. Aging cell 36 28752643
2022 Effects of CB2 Receptor Modulation on Macrophage Polarization in Pediatric Celiac Disease. Biomedicines 34 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
2002 Expression of CB2 cannabinoid receptor in Pichia pastoris. Protein expression and purification 31 12460775
2022 A peripheral CB2 cannabinoid receptor mechanism suppresses chemotherapy-induced peripheral neuropathy: evidence from a CB2 reporter mouse. Pain 30 35001054
2021 Cannabinoid receptor CB2 ablation protects against TAU induced neurodegeneration. Acta neuropathologica communications 30 34001284
2019 Allosteric modulators targeting cannabinoid cb1 and cb2 receptors: implications for drug discovery. Future medicinal chemistry 30 31517528
2016 PKCβII-mediated cross-talk of TRPV1/CB2 modulates the glucocorticoid-induced osteoclast overactivity. Pharmacological research 30 27919827
2010 Human platelets express authentic CB₁ and CB₂ receptors. Current neurovascular research 30 20854251
2006 Bacterial expression of functional, biotinylated peripheral cannabinoid receptor CB2. Protein expression and purification 30 16621595
2022 Cannabinoid CB2 Receptors in Neurodegenerative Proteinopathies: New Insights and Therapeutic Potential. Biomedicines 29 36551756
2016 Targeting the cannabinoid CB2 receptor to attenuate the progression of motor deficits in LRRK2-transgenic mice. Pharmacological research 29 27063942
2015 Palmitoylethanolamide attenuates PTZ-induced seizures through CB1 and CB2 receptors. Epilepsy research 29 26370914
2011 Effects of neuropeptide FF system on CB₁ and CB₂ receptors mediated antinociception in mice. Neuropharmacology 29 21945715
2018 Pharmacological regulation of cannabinoid CB2 receptor modulates the reinforcing and motivational actions of ethanol. Biochemical pharmacology 28 30063884
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 27 36417942
2012 Cannabinoid receptor CB2 protects against balloon-induced neointima formation. American journal of physiology. Heart and circulatory physiology 27 22227125
2004 Cannabinoids and intestinal motility: welcome to CB2 receptors. British journal of pharmacology 27 15277313
2019 The association of endocannabinoid receptor genes (CNR1 and CNR2) polymorphisms with depression: A meta-analysis. Medicine 26 31725603