{"id":"b706bae7-b625-5a5a-a1cf-a7f8760f204c","stable_key":"05a3cf47-e660-5ab3-8c32-5eba9847cf0a:thc-agonist-specific-trafficking","predicate":"activates","statement":"Cannabinoid receptors coupled to both Gs and Gi and could consequently stimulate or inhibit cAMP formation, with an identical rank order of agonist potency in both assays but markedly different intrinsic activities, anandamide and CP-55,940 being much less efficacious at stimulating cAMP than at inhibiting it, and forskolin enhancing the potency of some agonists a hundred-fold while not affecting others.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"positive","is_public":true,"mechanism_event_id":"d70b69d3-3fe6-5eaa-8635-1df9be02d265","mechanism_event_label":"The same receptor can push cAMP up as well as down, and which way depends on which drug is bound.","subject":{"id":"d092243c-94e9-5f03-a406-2fa245f2f4ae","slug":"cnr1","display_name":"Human cannabinoid receptor 1 / CB1 / CNR1","entity_type_key":"protein"},"object":{"id":"df55a90e-c550-5a67-8792-708984da79b1","slug":"camp-accumulation","display_name":"Cellular cyclic AMP accumulation","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"d70b69d3-3fe6-5eaa-8635-1df9be02d265","stable_key":"05a3cf47-e660-5ab3-8c32-5eba9847cf0a:thc-agonist-specific-trafficking-event","event_type":"biochemical_relationship","label":"The same receptor can push cAMP up as well as down, and which way depends on which drug is bound.","description":"Cannabinoid receptors coupled to both Gs and Gi and could consequently stimulate or inhibit cAMP formation, with an identical rank order of agonist potency in both assays but markedly different intrinsic activities, anandamide and CP-55,940 being much less efficacious at stimulating cAMP than at inhibiting it, and forskolin enhancing the potency of some agonists a hundred-fold while not affecting others.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"7d35f994-1912-5c7e-bda5-2f2c7bf14ac4","slug":"gs-protein","display_name":"Heterotrimeric Gs protein","entity_type_key":"protein"},"role":"alternative_partner","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"1a29cb8b-2916-5c74-a3d7-b2ae61fd37de","slug":"forskolin","display_name":"Forskolin","entity_type_key":"small_molecule"},"role":"test_condition","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"daf9c6ee-5fd9-529c-8dfb-f26606ae40e3","slug":"anandamide","display_name":"Anandamide / arachidonylethanolamide","entity_type_key":"small_molecule"},"role":"compared_ligand","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"5a9e5b75-e6aa-5684-ad62-8a8d60148c84","slug":"tetrahydrocannabinol","display_name":"Delta-9-tetrahydrocannabinol / THC","entity_type_key":"drug"},"role":"compared_ligand","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"d092243c-94e9-5f03-a406-2fa245f2f4ae","slug":"cnr1","display_name":"Human cannabinoid receptor 1 / CB1 / CNR1","entity_type_key":"protein"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"df55a90e-c550-5a67-8792-708984da79b1","slug":"camp-accumulation","display_name":"Cellular cyclic AMP accumulation","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":5,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/thc-research/9864268.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"a39487ffec2ec3efa585fd49076c7498e8db3bf0ab943fe267e431b93dc7483d\", \"start_char\": 0, \"end_char\": 1502, \"text_sha256\": \"a39487ffec2ec3efa585fd49076c7498e8db3bf0ab943fe267e431b93dc7483d\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Quantified potency and intrinsic activity of cannabinoid ligands on cAMP in CHO cells expressing human CB1","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"A ligand series measured for both stimulation and inhibition of cAMP, with and without forskolin","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Reports that the receptor couples to Gs as well as Gi and that ligands differ between the two pathways. It is a transfected overexpression system, where Gs coupling is more readily observed.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates.","comparator":null,"unit":null,"notes":"","entity":{"slug":"tetrahydrocannabinol","display_name":"Delta-9-tetrahydrocannabinol / THC","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Human receptor in CHO cells","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"The same receptor can push cAMP up as well as down, and which way depends on which drug is bound.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[thc-p9864268] Dual activation and inhibition of adenylyl cyclase by cannabinoid receptor agonists: evidence for agonist-specific trafficking of intracellular responses. (1998). https://pubmed.ncbi.nlm.nih.gov/9864268/ DOI: 10.1016/s0022-3565(24)37876-0","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Transfected cells","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"146cc349-b66f-5c8b-a919-08b6038f6996","evidence_kind":"source_excerpt","locator":"Lines 179-190","start_line":179,"end_line":190,"excerpt":"### thc-agonist-specific-trafficking\nCannabinoid receptors coupled to both Gs and Gi and could consequently stimulate or inhibit cAMP formation, with an identical rank order of agonist potency in both assays but markedly different intrinsic activities, anandamide and CP-55,940 being much less efficacious at stimulating cAMP than at inhibiting it, and forskolin enhancing the potency of some agonists a hundred-fold while not affecting others.\nCondition category: normal\nnutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates.\nplain_language: The same receptor can push cAMP up as well as down, and which way depends on which drug is bound.\norganism: Human receptor in CHO cells\ntissue_or_cell_type: Transfected cells\nexperimental_model: Quantified potency and intrinsic activity of cannabinoid ligands on cAMP in CHO cells expressing human CB1\nlimitations: Reports that the receptor couples to Gs as well as Gi and that ligands differ between the two pathways. It is a transfected overexpression system, where Gs coupling is more readily observed.\nexposure: A ligand series measured for both stimulation and inhibition of cAMP, with and without forskolin\nevidence_span: {\"source_cache\": \"artifacts/thc-research/9864268.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"a39487ffec2ec3efa585fd49076c7498e8db3bf0ab943fe267e431b93dc7483d\", \"start_char\": 0, \"end_char\": 1502, \"text_sha256\": \"a39487ffec2ec3efa585fd49076c7498e8db3bf0ab943fe267e431b93dc7483d\"}\n[thc-p9864268] Dual activation and inhibition of adenylyl cyclase by cannabinoid receptor agonists: evidence for agonist-specific trafficking of intracellular responses. (1998). https://pubmed.ncbi.nlm.nih.gov/9864268/ DOI: 10.1016/s0022-3565(24)37876-0","model_system":"Quantified potency and intrinsic activity of cannabinoid ligands on cAMP in CHO cells expressing human CB1","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [thc-p9864268] Dual activation and inhibition of adenylyl cyclase by cannabinoid receptor agonists: evidence for agonist-specific trafficking of intracellular responses. (1998). https://pubmed.ncbi.nlm.nih.gov/9864268/ DOI: 10.1016/s0022-3565(24)37876-0","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"b4367320-9724-507a-bead-6932fa0a78cb","stable_key":"import-05a3cf47-e660-5ab3-8c32-5eba9847cf0a","title":"THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"60abc81737d18b7a50b01ca487e38291774ee15d9777651aa2d3eac8670ac3b2","revision_id":"2cba3552-af89-580d-b20a-8cfb1b14f9e7","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[{"id":"04cff4fa-180f-5316-b0aa-948d37f286d0","title":"Does the cannabinoid receptor only inhibit adenylyl cyclase, or can it also stimulate it?","kind":"contradiction","status":"open","why":"The founding pharmacology established a pertussis-toxin-sensitive, Gi-mediated inhibition of adenylate cyclase, and that inhibition is the basis on which the receptor was identified and cloned. A later study in CHO cells expressing human CB1 reported coupling to Gs as well, with agonists differing in their relative efficacy at stimulating versus inhibiting cAMP, and called this agonist-specific trafficking. The systems differ: a neuroblastoma line with native receptor against a transfected line overexpressing human CB1, where Gs coupling is more readily observed. Whether the stimulatory arm operates at native receptor densities is not established here.","resolution":"Unresolved; needs review.","created_at":"2026-09-22 00:00:12","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/04cff4fa-180f-5316-b0aa-948d37f286d0","sides":[{"conflict_id":"04cff4fa-180f-5316-b0aa-948d37f286d0","ordinal":0,"label":"The drug turns down the enzyme that makes the cell’s main second messenger.","revision_id":"2cba3552-af89-580d-b20a-8cfb1b14f9e7","start_line":153,"end_line":164,"quote":"### thc-cannabinoid-inhibits-ac\nCannabinoids inhibited adenylate cyclase in neuroblastoma cell membranes with a pharmacology matching their psychoactivity.\nCondition category: normal\nnutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates.\nplain_language: The drug turns down the enzyme that makes the cell’s main second messenger.\norganism: Cultured neuroblastoma cells\ntissue_or_cell_type: Cell membranes\nexperimental_model: Cannabinoid pharmacology of adenylate cyclase in neuroblastoma cell membranes\nlimitations: One of the two founding pharmacology papers for Gi coupling. A transformed cell line, and cAMP is a proximal readout.\nexposure: Cannabinoid concentration-response on adenylate cyclase\nevidence_span: {\"source_cache\": \"artifacts/thc-research/6092901.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"996df269d90c0b0e02d12157d4ebc3dd16e6be5013bc741cf4ed9b798f0e7eb5\", \"start_char\": 0, \"end_char\": 1329, \"text_sha256\": \"996df269d90c0b0e02d12157d4ebc3dd16e6be5013bc741cf4ed9b798f0e7eb5\"}\n[thc-p6092901] Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes. (1984). https://pubmed.ncbi.nlm.nih.gov/6092901/ DOI: 10.1016/s0026-895x(25)15066-9","source_key":"import-05a3cf47-e660-5ab3-8c32-5eba9847cf0a","source_title":"THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21)","claim_ids":["f1c31d6d-1851-5e4b-9ed0-16d57b6d3362"]},{"conflict_id":"04cff4fa-180f-5316-b0aa-948d37f286d0","ordinal":1,"label":"The same receptor can push cAMP up as well as down, and which way depends on which drug is bound.","revision_id":"2cba3552-af89-580d-b20a-8cfb1b14f9e7","start_line":179,"end_line":190,"quote":"### thc-agonist-specific-trafficking\nCannabinoid receptors coupled to both Gs and Gi and could consequently stimulate or inhibit cAMP formation, with an identical rank order of agonist potency in both assays but markedly different intrinsic activities, anandamide and CP-55,940 being much less efficacious at stimulating cAMP than at inhibiting it, and forskolin enhancing the potency of some agonists a hundred-fold while not affecting others.\nCondition category: normal\nnutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates.\nplain_language: The same receptor can push cAMP up as well as down, and which way depends on which drug is bound.\norganism: Human receptor in CHO cells\ntissue_or_cell_type: Transfected cells\nexperimental_model: Quantified potency and intrinsic activity of cannabinoid ligands on cAMP in CHO cells expressing human CB1\nlimitations: Reports that the receptor couples to Gs as well as Gi and that ligands differ between the two pathways. It is a transfected overexpression system, where Gs coupling is more readily observed.\nexposure: A ligand series measured for both stimulation and inhibition of cAMP, with and without forskolin\nevidence_span: {\"source_cache\": \"artifacts/thc-research/9864268.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"a39487ffec2ec3efa585fd49076c7498e8db3bf0ab943fe267e431b93dc7483d\", \"start_char\": 0, \"end_char\": 1502, \"text_sha256\": \"a39487ffec2ec3efa585fd49076c7498e8db3bf0ab943fe267e431b93dc7483d\"}\n[thc-p9864268] Dual activation and inhibition of adenylyl cyclase by cannabinoid receptor agonists: evidence for agonist-specific trafficking of intracellular responses. (1998). https://pubmed.ncbi.nlm.nih.gov/9864268/ DOI: 10.1016/s0022-3565(24)37876-0","source_key":"import-05a3cf47-e660-5ab3-8c32-5eba9847cf0a","source_title":"THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21)","claim_ids":["b706bae7-b625-5a5a-a1cf-a7f8760f204c"]}]}],"corrections":[],"research":null}