Affinage

CNR1

Cannabinoid receptor 1 · UniProt P21554

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

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CNR1 (CB1) is a Gi/o-coupled seven-transmembrane receptor that serves as the principal neuronal mediator of endocannabinoid signaling, with additional critical roles in peripheral tissues including liver, vasculature, bone, reproductive organs, and skin. CB1 inhibits adenylate cyclase and activates MAPK cascades (ERK1/2, p38, JNK) through pertussis toxin-sensitive G proteins, and can additionally couple to Gq/11 in a ligand-selective manner to mobilize intracellular calcium via PLC and IP3/ryanodine receptor stores (PMID:2165569, PMID:16365309, PMID:10871313). Desensitization requires GRK3-mediated phosphorylation of C-terminal residues S426/S430 and β-arrestin 2 recruitment, while clathrin-dependent internalization depends on a distinct extreme C-terminal domain (PMID:10234009, PMID:10428044); structural studies have defined the orthosteric binding pocket and an extrahelical TM2-TM3-TM4 allosteric site where positive and negative modulators control TM2 rearrangements that determine G protein coupling efficacy (PMID:27768894, PMID:31659318, PMID:35637350). Cell-type-restricted CB1 populations exert distinct physiological functions—CB1 on glutamatergic terminals mediates neuroprotection against excitotoxicity, whereas CB1 on GABAergic neurons protects against age-dependent neurodegeneration and neuroinflammation—and CB1 forms functional heteromers with A2A, β2-adrenergic, CB2, GPR55, and Smoothened receptors that reshape downstream signaling (PMID:24843137, PMID:21690345, PMID:17356572, PMID:20590567, PMID:22532560, PMID:23161546).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1990 High

    Cloning of CB1 from rat brain established it as the first molecularly identified cannabinoid receptor and demonstrated that it is a GPCR that inhibits adenylate cyclase via pertussis toxin-sensitive G proteins, answering the long-standing question of how cannabinoids signal in the CNS.

    Evidence cDNA cloning, functional expression in cell lines with adenylate cyclase assays and radioligand binding

    PMID:2165569

    Open questions at the time
    • No structural information on the ligand-binding pocket
    • Downstream signaling beyond cAMP inhibition unknown
    • Endogenous ligand not yet identified at the time
  2. 1995 High

    Identification of an alternative splice variant (CB1A) and CB1-mediated immediate-early gene induction via a cAMP-independent pathway revealed that CB1 signaling extends beyond adenylate cyclase inhibition, opening the MAPK/transcriptional axis of cannabinoid signaling.

    Evidence RT-PCR/Northern blot for splice variants; Western blot and EMSA for krox-24 induction in astrocytoma cells with pertussis toxin sensitivity confirmed in CB1-transfected CHO cells

    PMID:7775459 PMID:7876112

    Open questions at the time
    • Functional consequences of CB1A isoform unknown
    • Specific MAPK cascade components not yet mapped
    • In vivo relevance of cAMP-independent signaling not established
  3. 1999 High

    Mutagenesis of the CB1 C-terminal tail resolved the paradox of how desensitization and internalization can be independently regulated: GRK3/β-arrestin 2 act on S426/S430 for desensitization, while a distinct extreme C-terminal domain governs clathrin-dependent internalization and recycling.

    Evidence Xenopus oocyte electrophysiology with GRK3/β-arrestin 2 co-expression and S426A/S430A mutagenesis; receptor internalization assays with C-terminal truncation mutants and hypertonic sucrose blockade

    PMID:10234009 PMID:10428044

    Open questions at the time
    • Phosphorylation sites for internalization not mapped
    • Endosomal sorting machinery not identified
    • In vivo desensitization kinetics unknown
  4. 2005 High

    Two studies expanded the signaling repertoire of CB1: lipid raft localization was shown to constrain CB1 signaling efficacy and enable raft-dependent apoptosis, while ligand-selective coupling to Gq/11 demonstrated that CB1 can mobilize intracellular calcium via PLC independently of Gi/o.

    Evidence Membrane fractionation and raft disruption with functional assays in C6 glioma; calcium photometry with dominant-negative Gαq, PLC/IP3R/RyR inhibitors in HEK293 and hippocampal neurons

    PMID:15657045 PMID:16365309

    Open questions at the time
    • Structural basis for ligand-selective G protein coupling unknown
    • Physiological triggers for Gq vs. Gi coupling not defined
    • Lipid raft dynamics in native neurons not characterized
  5. 2006 High

    Demonstration that CB1 promotes liver fibrosis via TGF-β1 and hepatic myofibroblast survival, with Cnr1 knockout or antagonism reducing fibrosis in three injury models, established CB1 as a major peripheral signaling axis in chronic liver disease.

    Evidence Cnr1 knockout mice and pharmacological CB1 antagonism in three chronic liver injury models; TGF-β1 measurement; human cirrhotic tissue immunohistochemistry

    PMID:16715087

    Open questions at the time
    • Direct CB1-expressing cell type in liver fibrosis pathway not conditionally targeted
    • Mechanism linking CB1 to TGF-β1 induction not resolved
    • Relevance to human fibrosis progression not tested prospectively
  6. 2008 High

    Three independent studies established diverse in vivo CB1 functions: constitutive CB1 activity tonically sensitizes TRPV1 nociceptive channels, CB1 is required for normal axonal growth and fasciculation during embryonic development, and CB1 deficiency causes preterm birth by deregulating the CRH-corticosterone endocrine axis.

    Evidence CB1 knockout mice with CGRP release and skin-nerve electrophysiology; morpholino knockdown in zebrafish plus chick embryo pharmacology; Cnr1 knockout mice with steroid hormone assays and CRH antagonist rescue

    PMID:18378465 PMID:18833324 PMID:18987195

    Open questions at the time
    • Molecular mechanism by which constitutive CB1 activity sensitizes TRPV1 not identified
    • Endocannabinoid ligand identity for axon guidance not defined
    • Human relevance of CB1-CRH axis in parturition not established
  7. 2010 High

    Discovery of CB1–β2-adrenoceptor heteromers by BRET showed that receptor heterodimerization remodels CB1 constitutive activity, surface trafficking, and signaling bias, validated in primary human trabecular meshwork cells.

    Evidence BRET in HEK293H cells; ERK and CREB phosphorylation assays; confirmation in primary human cells endogenously co-expressing both receptors

    PMID:20590567

    Open questions at the time
    • Stoichiometry and structure of the heteromer unknown
    • In vivo physiological consequences of CB1–β2AR heteromers not tested
    • Heteromer-selective pharmacology not developed
  8. 2012 High

    Identification of CB1–CB2 and CB1–GPR55 heteromers with distinct cross-talk properties (bidirectional cross-antagonism for CB1–CB2; asymmetric ERK/NFAT modulation for CB1–GPR55) demonstrated that heteromerization is a general mechanism diversifying cannabinoid receptor pharmacology.

    Evidence BRET, FRET, co-immunoprecipitation, neurite outgrowth and Akt/ERK assays in neuronal cells and rat brain tissue (CB1–CB2); BRET and transcription factor reporters in HEK293 (CB1–GPR55)

    PMID:22532560 PMID:23161546

    Open questions at the time
    • Native tissue stoichiometry and heteromer prevalence not quantified
    • Downstream effectors unique to heteromers vs. homomers not mapped
    • Therapeutic targeting of specific heteromers not achieved
  9. 2014 High

    Cell-type-specific conditional knockouts resolved a key question: CB1 on glutamatergic terminals mediates neuroprotection against excitotoxicity (including in Huntington models), while CB1 on GABAergic neurons prevents age-related hippocampal neurodegeneration and neuroinflammation—establishing that a single receptor exerts opposing circuit-level effects depending on cell type.

    Evidence Conditional Cnr1 knockout from glutamatergic vs. GABAergic neurons; quinolinic acid excitotoxicity and R6/2 Huntington models; Morris water maze; IL-6 and microglia immunohistochemistry

    PMID:21690345 PMID:24843137

    Open questions at the time
    • Intracellular signaling cascades in each cell type not compared
    • Whether circuit-level effects are purely presynaptic not resolved
    • Translation to human neurodegenerative disease not demonstrated
  10. 2016 High

    The first crystal structure of CB1 (with antagonist AM6538 at 2.8 Å) revealed the orthosteric binding pocket architecture and key ligand-contact residues, enabling rational interpretation of cannabinoid structure–activity relationships.

    Evidence X-ray crystallography at 2.8 Å resolution with molecular modeling and functional validation

    PMID:27768894

    Open questions at the time
    • Active-state structure not yet available at this point
    • Allosteric sites not structurally resolved
    • Membrane environment effects not captured in crystal
  11. 2019 High

    Crystal structure of the CB1–ORG27569–CP55940 ternary complex identified an extrahelical NAM site in the inner membrane leaflet overlapping a cholesterol-binding site, capturing an intermediate conformational state that explained how allosteric modulators decouple agonist binding from receptor activation.

    Evidence X-ray crystallography of ternary complex; mutagenesis; radioligand binding assays

    PMID:31659318

    Open questions at the time
    • Dynamic transitions between intermediate and active states not resolved
    • In vivo relevance of NAM-stabilized intermediate unknown
    • Selectivity determinants over CB2 at allosteric site not fully mapped
  12. 2022 High

    Structures of CB1 with PAM ZCZ011 at the same TM2-TM3-TM4 extrahelical site as the NAM, combined with MD simulations, revealed that PAM and NAM oppositely control TM2 rearrangement—the key conformational switch determining G protein coupling efficacy—providing a unified allosteric mechanism.

    Evidence X-ray crystallography and cryo-EM; molecular dynamics simulations; mutagenesis; functional assays

    PMID:35637350

    Open questions at the time
    • Whether TM2 rearrangement controls β-arrestin bias not determined
    • Allosteric cooperativity with orthosteric agonists quantified only for select ligands
    • Endogenous allosteric modulators of this site not identified
  13. 2023 High

    Active-state cryo-EM structure with an endocannabinoid analog showed that eCB-specific contacts with toggle-switch residues F200/W356 and TM2 drive the G protein activation-determining TM2 rearrangement unique to CB1, explaining how endocannabinoids exploit a receptor-specific activation mechanism.

    Evidence Cryo-EM of active CB1-Gi complex; docking; MD simulations; mutagenesis and Gα signaling assays

    PMID:37160876

    Open questions at the time
    • Full signaling complex including β-arrestin not yet structurally resolved
    • How distinct endocannabinoids (AEA vs. 2-AG) produce differential TM2 conformations is unclear
    • Integration of allosteric and orthosteric structural data into predictive pharmacology models incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: how CB1 heteromer stoichiometry and tissue-specific assembly determine pharmacological outcomes in vivo; the structural basis for ligand-biased Gi vs. Gq coupling; whether endogenous allosteric modulators of the TM2-TM3-TM4 site exist; and how cell-type-specific CB1 signaling cascades produce opposing circuit-level phenotypes in the CNS.
  • Heteromer-selective therapeutics not developed
  • Endogenous allosteric modulators unknown
  • β-arrestin-biased structural states not captured

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 5 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-112316 Neuronal System 5 R-HSA-1266738 Developmental Biology 3 R-HSA-1474165 Reproduction 2
Partners
ADORA2AADRB2ARRB2CNR2GPR55GRK3SMOTRPV1

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 CB1 (CNR1) was cloned from rat brain cDNA and identified as a G protein-coupled receptor with seven transmembrane helices that inhibits adenylate cyclase activity in a dose-dependent, stereoselective, and pertussis toxin-sensitive manner, establishing it as the neuronal receptor mediating cannabis effects. cDNA cloning, functional expression in cell lines, adenylate cyclase inhibition assay, radioligand binding Nature High 2165569
1991 Human CB1 receptor cDNA was cloned from brain and testis; the protein shares 97.3% identity with rat CB1, and stably transfected CHO-K1 cells show dose-dependent, stereoselective inhibition of forskolin-induced cAMP accumulation upon cannabinoid agonist treatment, confirming functional coupling to Gi. cDNA cloning from human brain cDNA library, stable transfection in CHO-K1 cells, cAMP assay, radioligand binding ([3H]CP55940) The Biochemical journal High 1718258
1995 Alternative splicing of the human CNR1 gene produces a shorter isoform (CB1A) lacking 61 N-terminal amino acids (with a distinct 28 amino acid N-terminus), present at up to 20% of CB1 levels in brain and peripheral tissues; a similar splice variant exists in rat. RT-PCR of human and rat cDNA libraries, cDNA sequencing, Northern blot The Journal of biological chemistry High 7876112
1995 CB1 receptor activation by the cannabinoid agonist CP-55940 in human astrocytoma cells (U373 MG) induces expression of the immediate-early gene krox-24 (egr-1/NGFI-A) via a pertussis toxin-sensitive G-protein pathway independent of cAMP metabolism; this was confirmed in CHO cells transfected with human CB1. Western blot, EMSA, pertussis toxin treatment, CHO cell transfection with human CB1, CB1 antagonist SR141716A blockade The Journal of biological chemistry High 7775459
1999 CB1 receptors undergo rapid agonist-induced internalization via clathrin-coated pits; internalization does not require activated Gαi, Gαo, or Gαs subunits; a region of the extreme C-terminus (last 14 residues) is necessary for internalization. Recycling of internalized CB1 to the cell surface requires endosomal acidification and dephosphorylation. Receptor internalization assays, hypertonic sucrose blockade, C-terminal truncation mutants, pharmacological tools in heterologous expression system Journal of neurochemistry High 10428044
1999 GRK3 and β-arrestin 2 mediate homologous CB1 receptor desensitization in Xenopus oocytes; phosphorylation of S426 or S430 in the C-terminal tail is required for desensitization but not for internalization, establishing distinct molecular domains for these two regulatory processes. Xenopus oocyte electrophysiology (Kir3 current), co-expression of GRK3/β-arrestin 2, site-directed mutagenesis of S426A and S430A, CB1 C-terminal truncation mutants The Journal of neuroscience High 10234009
2000 CB1 receptor activation mediates cell migration (chemotaxis and chemokinesis) in HEK293 cells via pertussis toxin-sensitive Gi proteins; the migratory response requires MAPK activation but not adenylate cyclase inhibition. Boyden chamber migration assay with stable CB1-expressing HEK293 cells, pertussis toxin treatment, MEK inhibitor PD098059, CB1 antagonist SR141716A, checkerboard analysis The Journal of pharmacology and experimental therapeutics High 10871313
2005 CB1 receptors are localized in lipid raft microdomains in C6 glioma cells; disruption of lipid rafts with methyl-β-cyclodextrin (MCD) approximately doubles CB1 binding efficiency and amplifies CB1-dependent signaling via adenylate cyclase and p42/p44 MAPK; CB1 activation within rafts underlies anandamide-induced apoptosis and cytochrome c release. Membrane fractionation, [35S]GTPγS binding assay, adenylate cyclase assay, MAPK phosphorylation, apoptosis assay (cytochrome c release), methyl-β-cyclodextrin disruption of rafts The Journal of biological chemistry High 15657045
2005 CB1 receptor activation by WIN55,212-2 increases intracellular calcium via coupling to Gq/11 proteins and phospholipase C, releasing calcium from IP3- and ryanodine receptor-sensitive intracellular stores; this Gq-mediated calcium mobilization is WIN-specific and not triggered by other cannabinoid agonist classes (THC, CP55940, anandamide, HU-210). Calcium photometry in CB1-expressing HEK293 cells and hippocampal neurons, pertussis toxin pretreatment, dominant-negative Gαq expression, PLC inhibitors, IP3 receptor and ryanodine receptor inhibitors Proceedings of the National Academy of Sciences High 16365309
2004 Human sperm express CB1 (but not CB2) receptor, localized to the sperm head and midpiece; CB1 activation by anandamide reduces sperm motility, inhibits capacitation-induced acrosome reaction, causes rapid plasma membrane hyperpolarization, and reduces mitochondrial activity, all reversed by CB1 antagonist SR141716A. RT-PCR, Western blot, anandamide treatment with CB1 antagonist, rhodamine 123 fluorescence (mitochondrial activity), intracellular calcium measurement, K+ channel blockade The Journal of clinical endocrinology and metabolism High 15562018
2007 Striatal CB1 and adenosine A2A receptors form heteromeric complexes demonstrated in co-transfected HEK-293T cells and rat striatum; CB1 receptor signaling in a neuroblastoma cell line is completely dependent on A2A receptor activation, and intrastriatal A2A receptor blockade counteracts cannabinoid-induced motor depression. Co-immunoprecipitation, co-localization immunofluorescence in striatum, bimolecular fluorescence complementation, cAMP assays, in vivo intrastriatal pharmacology Neuropsychopharmacology High 17356572
2009 CB1 receptors promote oxidative stress and cardiomyocyte cell death via reactive oxygen species generation and activation of p38 and JNK MAPK pathways; CB1 knockout mice show markedly attenuated doxorubicin-induced cardiac dysfunction and cell death, and CB1 agonists (AEA, HU210) enhance doxorubicin-induced MAPK activation and cell death in human primary cardiomyocytes. CB1 knockout mice, pressure-volume conductance system (cardiac function), MAPK activation (Western blot), flow cytometry (ROS, cell death), co-administration of CB1 agonists/antagonists and MAPK inhibitors in human cardiomyocytes Cardiovascular research High 19942623
2010 CB1 and β2-adrenoceptors form physical heteromers (demonstrated by BRET) in HEK293H cells; co-expression reduces CB1 constitutive activity, increases CB1 cell surface expression, and alters signaling: enhancing Gαi-dependent ERK phosphorylation but decreasing non-Gαi-mediated CREB phosphorylation; similar functional interactions occur in primary human trabecular meshwork cells endogenously co-expressing both receptors. BRET, receptor trafficking assays, ERK phosphorylation, CREB phosphorylation, CB1 inverse agonist AM251 vs. neutral antagonist O-2050 pharmacology British journal of pharmacology High 20590567
2011 CB1 receptor activation by AEA (but not 2-AG unless MAGL is inhibited) suppresses RhoA GTPase activity in prostate carcinoma cells, causing loss of actin/myosin microfilaments and reduced cell migration; CB1 antagonism (AM251) increases RhoA activity and promotes migration, indicating constitutive endocannabinoid-CB1 tone chronically represses RhoA. RhoA/Rac1/Cdc42 activity pull-down assays, CB1 agonist/antagonist treatment (WIN55212, AM251), MAGL inhibitor JZL184, actin/myosin staining, Boyden chamber migration assay Endocrinology High 22087025
2012 CB1 and CB2 cannabinoid receptors form heteromers in transfected neuronal cells and in rat brain regions (pineal gland, nucleus accumbens, globus pallidus); within these heteromers, co-activation of CB1 and CB2 produces negative cross-talk in Akt phosphorylation and neurite outgrowth, and CB1 antagonists can block CB2 agonist effects and vice versa (bidirectional cross-antagonism). BRET, FRET, co-immunoprecipitation, neurite outgrowth assay, Akt phosphorylation, rat brain tissue biochemistry The Journal of biological chemistry High 22532560
2012 GPR55 and CB1 receptors form heteromers in HEK293 cells; co-expression of CB1 specifically inhibits GPR55-mediated transcription factor activation (NFAT, SRE) and ERK1/2 phosphorylation, while GPR55 presence enhances CB1-mediated ERK1/2 and NFAT activation; internalization of both receptors is unaffected by heteromerization. Co-immunoprecipitation, BRET, transcription factor activation assays (NFAT, SRE luciferase), ERK1/2 phosphorylation, receptor internalization assays in HEK293 cells The Journal of biological chemistry High 23161546
2016 Crystal structure of human CB1 in complex with the antagonist AM6538 determined at 2.8 Å resolution, revealing the orthosteric binding pocket architecture and key residues for antagonist/agonist interactions; combined with molecular modeling, the structure explains binding modes of THC and synthetic cannabinoids. X-ray crystallography (2.8 Å), molecular modeling, functional studies Cell High 27768894
2019 Crystal structure of CB1 bound to the negative allosteric modulator (NAM) ORG27569 and agonist CP55940 reveals the NAM binds to an extrahelical site within the inner membrane leaflet overlapping a conserved cholesterol-binding site in class A GPCRs; the ternary complex captures an intermediate state where aromatic residues at the base of the agonist-binding pocket adopt an inactive conformation despite orthosteric pocket contraction. X-ray crystallography (ternary complex structure), mutagenesis, radioligand binding assays Nature chemical biology High 31659318
2022 Cryo-EM and crystal structures of CB1 bound to positive allosteric modulator (PAM) ZCZ011 show it binds to an extrahelical TM2-TM3-TM4 site; molecular dynamics simulations and mutagenesis reveal TM2 rearrangement is critical for allosteric signal propagation — PAM ZCZ011 promotes TM2 rearrangement favoring receptor activation, while NAM ORG27569 (binding the same site) impedes TM2 rearrangement. X-ray crystallography, cryo-EM, molecular dynamics simulations, mutagenesis, functional assays Nature chemical biology High 35637350
2023 Cryo-EM structure of CB1 in active signaling complex with the endocannabinoid analog AMG315 (anandamide analog) reveals eCB-specific binding pocket features; ligand interactions with 'toggle switch' residues F200(3.36) and W356(6.48) and with TM2 drive intracellular TM2 rearrangements that determine G protein activation efficacy — these TM2 changes are unique to CB1 and are exploited by CB1-specific allosteric modulators. Cryo-EM, docking, molecular dynamics simulations, mutagenesis, Gα signaling assays Nature communications High 37160876
2008 CB1 receptor is required for normal axonal growth and fasciculation during embryonic development; pharmacological inhibition of CB1 in chick embryos and morpholino-mediated knockdown in zebrafish both caused defects in axon pathfinding and fasciculation, coincident with expression of enzymes for 2-AG synthesis in overlapping patterns. CB1 pharmacological inhibition in chick embryo, morpholino knockdown in zebrafish, immunohistochemistry, in situ hybridization Molecular and cellular neurosciences Medium 18378465
2008 Loss of CB1 (Cnr1−/−) induces preterm birth in mice; CB1 deficiency alters progesterone/estrogen ratios prior to parturition and causes aberrant corticotropin-releasing hormone (CRH) and corticosterone secretion; CRH antagonist rescues normal parturition timing in Cnr1−/− mice, and excess corticosterone induces preterm birth in wild-type mice, placing CB1 upstream of the CRH-driven endocrine axis in labor regulation. Cnr1 knockout mice (genetic), radioimmunoassay of steroid hormones, CRH antagonist treatment, corticosterone administration in WT mice, Ptgs1/Cnr1 double-knockout epistasis PloS one High 18833324
2006 CB1 receptor antagonism (SR141716A) in mice and Cnr1−/− mice reduces liver fibrosis progression in three chronic liver injury models; CB1 activation by endocannabinoids promotes fibrogenesis by increasing hepatic TGF-β1 and by promoting survival and proliferation of hepatic myofibroblasts; CB1 is highly induced in human cirrhotic liver and in liver fibrogenic cells. Cnr1 knockout mice, CB1 antagonist SR141716A in three chronic liver injury models, TGF-β1 measurement, fibrogenic cell apoptosis/proliferation assays, human cirrhotic tissue immunohistochemistry Nature medicine High 16715087
2011 Genetic and siRNA-mediated inactivation of CB1 receptors inhibits bFGF-induced endothelial proliferation, migration, and tube formation through prosurvival/migratory pathways involving ERK, Akt, FAK, JNK, Rho, and MMP-2; CB1 blockade inhibits neovascular growth in rabbit cornea and reduces pathologic neovascularization in mouse oxygen-induced retinopathy in vivo. siRNA knockdown of CB1, CB1 antagonist pharmacology, endothelial proliferation/migration/tube formation assays, ERK/Akt/FAK/JNK/Rho/MMP-2 pathway analysis, rabbit cornea neovascularization assay, mouse oxygen-induced retinopathy model Blood High 21460248
2011 CB1 receptor activity on hippocampal GABAergic (but not glutamatergic) neurons protects against age-dependent cognitive decline, pyramidal cell degeneration, and neuroinflammation; conditional deletion of CB1 from forebrain GABAergic neurons replicates the hippocampal neuron loss and elevated IL-6/microglial activation seen in complete Cnr1−/− mice. Conditional Cnr1 knockout (GABAergic vs. glutamatergic specific), Morris water maze, neuronal counting, IL-6 ELISA, immunohistochemistry for astrocytes and microglia Proceedings of the National Academy of Sciences High 21690345
2014 CB1 receptors on glutamatergic (but not GABAergic) corticostriatal terminals are the essential population mediating neuroprotective effects of cannabinoids; conditional deletion of CB1 from glutamatergic neurons removes neuroprotection against quinolinic acid excitotoxicity and in the R6/2 Huntington disease model, while GABAergic CB1 deletion does not. Conditional Cnr1 knockout (glutamatergic vs. GABAergic), quinolinic acid excitotoxicity model, R6/2 Huntington mouse model, DREADD pharmacogenetic remote manipulation of corticostriatal projections Proceedings of the National Academy of Sciences High 24843137
2013 CB1 activation in neural stem cells (NSCs) via anandamide or ACEA (CB1-specific agonist but not CB2-specific agonist) enhances neuronal differentiation and maturation via long-term inhibition of the ERK1/2 pathway; pharmacological ERK1/2 inhibition mimics CB1-driven neuronal differentiation; CB1 activation also upregulates neuronal differentiation genes and suppresses stemness genes. NSC differentiation assays (ALP activity, morphometric neurite analysis), ERK1/2 phosphorylation assay, selective CB1/CB2 agonists and antagonists, gene array profiling, RT-PCR and Western blot PloS one High 23372698
2017 CB1 receptor activation in human bone marrow MSCs enhances osteogenic differentiation by increasing mitochondrial energy metabolism (oxygen consumption rate, mitochondrial membrane potential) and Nrf1/Nrf2 expression; CB1 activates JNK and p38 MAPK pathways while inhibiting Erk1/2, and CB1 can rescue impaired osteogenic differentiation caused by mitochondrial electron transport chain inhibition. Alkaline phosphatase assay, alizarin red staining, Seahorse Mito Stress Test (OCR), JC-10 MMP assay, Western blot for signaling kinases, rotenone and CoQ10 pharmacology, CB1 siRNA knockdown Stem cell research & therapy Medium 35063024
2019 Cannabinoids (Δ9-THC, HU-210, CP55940) inhibit Sonic Hedgehog signaling by blocking Smoothened (Smo) function; proximity ligation assays identified CB1-Smo heteromers in vivo, suggesting allosteric CB1-Smo interactions underlie CB-induced craniofacial and brain developmental defects in mice and zebrafish; a CB1 antagonist attenuated cannabinoid-induced birth defects. Mouse and zebrafish developmental models, Shh pathway reporter assays, proximity ligation assay (CB1-Smo heteromers), CB1 antagonist rescue experiments Scientific reports Medium 31690747
2017 Cannabidiol-induced melanogenesis in human epidermal melanocytes is mediated by CB1 receptor (not CB2), acting through phosphorylation of p38 MAPK and p42/44 MAPK to upregulate MITF gene expression and downstream melanogenic enzymes (tyrosinase, TRP1, TRP2), independently of cAMP-PKA signaling. Melanin content assay, tyrosinase activity assay, CB1/CB2 selective antagonists, kinase inhibitors, RT-PCR and Western blot in human melanocytes Chemico-biological interactions Medium 28601556
2008 CB1 receptor constitutive activity maintains TRPV1 channels in a sensitized state responsive to capsaicin; CB1 knockout mice show markedly reduced capsaicin-evoked CGRP release from spinal cord and reduced action potential firing in isolated skin-nerve preparations, without differences in TRPV1 expression; CB1 inverse agonists inhibit capsaicin-induced calcium influx and nociceptive flinching. CB1 knockout mice, capsaicin-evoked CGRP release from spinal cord tissue, skin-nerve electrophysiology, calcium influx assay in F-11 cells, nociceptive behavioral tests, galanin/bradykinin sensitization rescue The Journal of neuroscience High 18987195

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1990 Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 3947 2165569
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
1997 Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacology & therapeutics 1197 9336020
2001 Molecular phylogenetics and the origins of placental mammals. Nature 862 11214319
2002 An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proceedings of the National Academy of Sciences of the United States of America 692 12060783
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
1991 Molecular cloning of a human cannabinoid receptor which is also expressed in testis. The Biochemical journal 535 1718258
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2006 CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Nature medicine 430 16715087
2006 Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes 430 17065342
2016 Crystal Structure of the Human Cannabinoid Receptor CB1. Cell 422 27768894
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2002 The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met. Nature 371 11894096
2004 Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life sciences 357 15670612
2003 Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. The Journal of clinical investigation 311 12511587
2005 The cannabinoid agonist WIN55,212-2 increases intracellular calcium via CB1 receptor coupling to Gq/11 G proteins. Proceedings of the National Academy of Sciences of the United States of America 266 16365309
2009 Signal transduction of the CB1 cannabinoid receptor. Journal of molecular endocrinology 259 19620237
1988 Presence of three distinct molecular species of Gi protein alpha subunit. Structure of rat cDNAs and human genomic DNAs. The Journal of biological chemistry 256 2834384
2017 CB1 and CB2 Receptor Pharmacology. Advances in pharmacology (San Diego, Calif.) 254 28826534
1995 An amino-terminal variant of the central cannabinoid receptor resulting from alternative splicing. The Journal of biological chemistry 247 7876112
1999 Internalization and recycling of the CB1 cannabinoid receptor. Journal of neurochemistry 243 10428044
2003 The DNA sequence and analysis of human chromosome 6. Nature 242 14574404
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
2010 CB(1) cannabinoid receptors and their associated proteins. Current medicinal chemistry 223 20166926
2009 Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome. Autism research : official journal of the International Society for Autism Research 223 19598235
1999 Distinct domains of the CB1 cannabinoid receptor mediate desensitization and internalization. The Journal of neuroscience : the official journal of the Society for Neuroscience 209 10234009
2009 CB1 and CB2 cannabinoid receptors differentially regulate the production of reactive oxygen species by macrophages. Cardiovascular research 207 19596672
2004 CB1 cannabinoid receptors mediate anxiolytic effects: convergent genetic and pharmacological evidence with CB1-specific agents. Behavioural pharmacology 202 15252281
2007 Striatal adenosine A2A and cannabinoid CB1 receptors form functional heteromeric complexes that mediate the motor effects of cannabinoids. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 200 17356572
2004 Human cannabinoid receptor 1: 5' exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse. Molecular psychiatry 195 15289816
2012 Cannabinoid receptors CB1 and CB2 form functional heteromers in brain. The Journal of biological chemistry 192 22532560
2008 Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience 192 18354002
2004 Human sperm express cannabinoid receptor Cb1, the activation of which inhibits motility, acrosome reaction, and mitochondrial function. The Journal of clinical endocrinology and metabolism 187 15562018
2003 Ontogenetic development of cannabinoid receptor expression and signal transduction functionality in the human brain. The European journal of neuroscience 183 12752773
2008 Reduced cortical cannabinoid 1 receptor messenger RNA and protein expression in schizophrenia. Archives of general psychiatry 182 18606950
2001 Cannabinoids inhibit emesis through CB1 receptors in the brainstem of the ferret. Gastroenterology 180 11606489
2009 CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes. Cardiovascular research 178 19942623
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