id: MODULE:opioid_receptor_signaling title: G protein-coupled opioid receptor signaling pathway module description: >- The G protein-coupled opioid receptor signaling pathway (GO:0038003) and its canonical adenylate cyclase-inhibiting branch (GO:0031635) are initiated when endogenous opioid and opioid-like neuropeptide precursors — proenkephalin-A (PENK, PANTHER:PTHR11438:SF3; cleaved into Met-enkephalin, Leu-enkephalin, Met-enkephalin-Arg-Phe, and Met-enkephalin-Arg-Gly-Leu), proenkephalin-B / prodynorphin (PDYN, PANTHER:PTHR11438:SF4; cleaved into dynorphin A, dynorphin B, alpha-/beta-neoendorphin, and Leu-enkephalin), and prepronociceptin (PNOC, PANTHER:PTHR11438:SF2; cleaved into nociceptin / orphanin FQ), together with pro-opiomelanocortin-derived beta-endorphin — are secreted from neuronal dense-core vesicles and bind the seven-transmembrane opioid receptor family GPCRs OPRM1 (mu-type opioid receptor, PANTHER:PTHR24229:SF7), OPRD1 (delta-type opioid receptor, PANTHER:PTHR24229:SF2), OPRK1 (kappa-type opioid receptor, PANTHER:PTHR24229:SF1), and OPRL1 (nociceptin/NOP receptor, PANTHER:PTHR24229:SF11) at the plasma membrane and synaptic membrane. Agonist-bound opioid receptors couple to pertussis-toxin-sensitive inhibitory heterotrimeric Gi/o proteins (exemplified by GNAI1, PANTHER:PTHR10218:SF359), inhibiting adenylate cyclase (exemplified by ADCY5, PANTHER:PTHR45627:SF7) to lower intracellular cAMP while released Gbeta-gamma dimers activate GIRK potassium channels and inhibit voltage-gated Ca2+ channels to suppress presynaptic neurotransmitter release and nociceptive transmission. status: DRAFT evidence: - source_id: GO:0038003 title: G protein-coupled opioid receptor signaling pathway statement: >- The module is grounded in the GO biological process term for the G protein-coupled opioid receptor signaling pathway (GO:0038003) and its canonical adenylate cyclase-inhibiting branch (GO:0031635). - source_id: GO:0031635 title: adenylate cyclase-inhibiting opioid receptor signaling pathway statement: >- Models the canonical Gi/o-coupled adenylate cyclase-inhibiting opioid receptor signaling cascade (GO:0031635) triggered by endogenous opioid peptides (PENK, PDYN, PNOC) across OPRM1, OPRD1, OPRK1, and OPRL1. - source_id: Reactome:R-HSA-111885 title: Opioid Signalling supporting_text: >- Opioid action is mediated by the receptors for endogenous opioids; peptides such as the enkephalins, the endorphins or the dynorphins. Opioids possess powerful analgesic and sedative effects, and are widely used as pain-killers. Their main side-effect is the rapid establishment of a strong addiction. Opioids receptors are G-protein coupled receptors (GPCR). There are four classes of receptors: mu (MOR), kappa (KOR) and delta (DOR), and the nociceptin receptor (NOP). statement: >- Establishes that endogenous opioid peptides (enkephalins, endorphins, dynorphins) signal through the four classes of G protein-coupled opioid receptors (OPRM1/MOR, OPRD1/DOR, OPRK1/KOR, and OPRL1/NOP). - source_id: Reactome:R-HSA-418594 title: G alpha (i) signalling events supporting_text: >- The classical signalling mechanism for G alpha (i) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase (Dessauer C W et al. 2002). Decreased production of cAMP from ATP results in decreased activity of cAMP-dependent protein kinases. statement: >- Establishes that activated Gi/o alpha subunits inhibit adenylate cyclase and decrease intracellular cAMP and cAMP-dependent protein kinase activity. - source_id: PMID:7057924 title: Primary structure of the human Met- and Leu-enkephalin precursor and its mRNA. supporting_text: >- The corresponding amino acid sequence shows that the precursor is 267 amino acids long and contains six interspersed Met-enkephalin sequences and one Leu-enkephalin sequence. Five of the seven enkephalins are flanked on both sides by pairs of basic amino acid residues. statement: >- Demonstrates that human PENK encodes a polyprotein precursor yielding six Met-enkephalin and one Leu-enkephalin opioid peptides. - source_id: PMID:9047294 title: NMR and structural model of dynorphin A (1-17) bound to dodecylphosphocholine micelles. supporting_text: >- Dynorphin A (1-17) (dynorphin) acts preferentially and with high affinity at the kappa-opioid receptor, for which it is the natural, endogenous ligand. statement: >- Establishes PDYN-derived dynorphin A(1-17) as the high-affinity endogenous agonist of the kappa-opioid receptor (OPRK1). - source_id: PANTHER:PTN000153716 title: PAINT node PTN000153716 for the proenkephalin/prodynorphin/pronociceptin family (PTHR11438) statement: >- Local PAINT IBD root node in PTHR11438 with propagated terms C:GO:0043025, F:GO:0001515, F:GO:0031628, P:GO:0007218, P:GO:0019233; PAINT date 20260828. notes: >- Curated signaling-pathway module for the G protein-coupled opioid receptor signaling pathway (GO:0038003) and its adenylate cyclase-inhibiting branch (GO:0031635) built with PANTHER FAMILY/subfamily selectors across the endogenous proenkephalin-family opioid peptide ligands PENK (PANTHER:PTHR11438:SF3), PDYN (PANTHER:PTHR11438:SF4), and PNOC (PANTHER:PTHR11438:SF2), their cognate GPCRs OPRM1 (PANTHER:PTHR24229:SF7), OPRD1 (PANTHER:PTHR24229:SF2), OPRK1 (PANTHER:PTHR24229:SF1), and OPRL1 (PANTHER:PTHR24229:SF11), and downstream Gi/o alpha (GNAI1, PANTHER:PTHR10218:SF359) and adenylate cyclase (ADCY5, PANTHER:PTHR45627:SF7) effectors. module: id: opioid_receptor_signaling label: G protein-coupled opioid receptor signaling pathway module_type: SIGNALING_PATHWAY concepts: - preferred_term: G protein-coupled opioid receptor signaling pathway term: id: GO:0038003 label: G protein-coupled opioid receptor signaling pathway description: >- The series of molecular signals generated as a consequence of a G protein-coupled opioid receptor (OPRM1, OPRD1, OPRK1, or OPRL1) binding to one of its physiological opioid peptide ligands. - preferred_term: adenylate cyclase-inhibiting opioid receptor signaling pathway term: id: GO:0031635 label: adenylate cyclase-inhibiting opioid receptor signaling pathway description: >- A G protein-coupled opioid receptor signaling pathway in which ligand-activated opioid receptors couple to Gi/o proteins to inhibit adenylate cyclase and reduce intracellular cAMP concentration. context: taxa: - preferred_term: Euteleostomi term: id: NCBITaxon:117571 label: Euteleostomi cellular_components: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol parts: - order: 1 role: endogenous opioid peptide ligand-receptor engagement node: id: opioid_receptor_engagement label: PENK-, PDYN-, and PNOC-derived opioid peptide engagement of OPRM1, OPRD1, OPRK1, and OPRL1 module_type: REGULATORY_STEP description: >- Secreted mature opioid peptides cleaved from proenkephalin-A (PENK: Met- and Leu-enkephalins), prodynorphin (PDYN: dynorphins A/B and neoendorphins), and prepronociceptin (PNOC: nociceptin/orphanin FQ) bind the orthosteric pockets of their cognate seven-transmembrane opioid receptors OPRD1 (delta), OPRM1 (mu), OPRK1 (kappa), and OPRL1 (nociceptin/NOP) at the plasma membrane and synaptic membrane via their N-terminal Tyr1/Phe1-Gly2-Gly3-Phe4 message sequence. annotons: - id: penk_proenkephalin_ligand label: PENK proenkephalin-A opioid peptide ligand participant: selector_type: FAMILY family: preferred_term: Proenkephalin-A subfamily term: id: PANTHER:PTHR11438:SF3 label: PROENKEPHALIN-A representative_members: - preferred_term: PENK term: id: UniProtKB:P01210 label: Proenkephalin-A ancestral_nodes: - preferred_term: PAINT node PTN000153716 for the proenkephalin family term: id: PANTHER:PTN000153716 label: PTN000153716 description: >- Local PAINT IBD root node in PTHR11438 with propagated terms C:GO:0043025, F:GO:0001515, F:GO:0031628, P:GO:0007218, P:GO:0019233; PAINT date 20260828. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000153716 in PTHR11438. evidence: - source_id: file:interpro/panther/PTHR11438/PTHR11438-review.yaml title: PTHR11438 PANTHER family review statement: >- PTHR11438 review confirms family-wide GO:0001515 (opioid peptide activity), GO:0038003 (G protein-coupled opioid receptor signaling pathway), and GO:0031635 (adenylate cyclase-inhibiting opioid receptor signaling pathway) across SF3 (PENK), SF4 (PDYN), and SF2 (PNOC). function: preferred_term: opioid peptide activity term: id: GO:0001515 label: opioid peptide activity processes: - preferred_term: G protein-coupled opioid receptor signaling pathway term: id: GO:0038003 label: G protein-coupled opioid receptor signaling pathway - preferred_term: adenylate cyclase-inhibiting opioid receptor signaling pathway term: id: GO:0031635 label: adenylate cyclase-inhibiting opioid receptor signaling pathway locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Endogenous opioid polyprotein precursor processed into Met-enkephalin and Leu-enkephalin pentapeptides (and C-terminally extended heptapeptide/octapeptide agonists) that preferentially bind and activate delta (OPRD1) and mu (OPRM1) opioid receptors to initiate Gi/o-coupled adenylate cyclase-inhibiting opioid receptor signaling. evidence: - source_id: PMID:7057924 title: Primary structure of the human Met- and Leu-enkephalin precursor and its mRNA. supporting_text: >- The corresponding amino acid sequence shows that the precursor is 267 amino acids long and contains six interspersed Met-enkephalin sequences and one Leu-enkephalin sequence. statement: >- Establishes human PENK as the precursor of endogenous Met- and Leu-enkephalin opioid receptor agonists. - source_id: Reactome:R-HSA-418594 title: G alpha (i) signalling events supporting_text: >- The classical signalling mechanism for G alpha (i) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase (Dessauer C W et al. 2002). statement: >- Demonstrates that PENK-derived opioid peptides signal through Gi/o-coupled opioid receptors to inhibit adenylate cyclase. - id: pdyn_prodynorphin_ligand label: PDYN prodynorphin (proenkephalin-B) opioid peptide ligand participant: selector_type: FAMILY family: preferred_term: Proenkephalin-B (prodynorphin) subfamily term: id: PANTHER:PTHR11438:SF4 label: PROENKEPHALIN-B representative_members: - preferred_term: PDYN term: id: UniProtKB:P01213 label: Proenkephalin-B evidence: - source_id: file:interpro/panther/PTHR11438/PTHR11438-review.yaml title: PTHR11438 PANTHER family review statement: >- PTHR11438 review confirms family-wide GO:0001515 (opioid peptide activity), GO:0038003 (G protein-coupled opioid receptor signaling pathway), and GO:0031635 (adenylate cyclase-inhibiting opioid receptor signaling pathway) across SF3 (PENK), SF4 (PDYN), and SF2 (PNOC). function: preferred_term: opioid peptide activity term: id: GO:0001515 label: opioid peptide activity processes: - preferred_term: G protein-coupled opioid receptor signaling pathway term: id: GO:0038003 label: G protein-coupled opioid receptor signaling pathway - preferred_term: adenylate cyclase-inhibiting opioid receptor signaling pathway term: id: GO:0031635 label: adenylate cyclase-inhibiting opioid receptor signaling pathway locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Endogenous opioid polyprotein precursor processed into dynorphin A, dynorphin B, and alpha-/beta-neoendorphin peptides that preferentially bind and activate the kappa-opioid receptor (OPRK1; and with lower selectivity OPRM1 and OPRD1) to initiate Gi/o-coupled adenylate cyclase-inhibiting opioid receptor signaling. evidence: - source_id: PMID:9047294 title: NMR and structural model of dynorphin A (1-17) bound to dodecylphosphocholine micelles. supporting_text: >- Dynorphin A (1-17) (dynorphin) acts preferentially and with high affinity at the kappa-opioid receptor, for which it is the natural, endogenous ligand. statement: >- Establishes PDYN-derived dynorphin A as the endogenous high-affinity agonist of OPRK1. - source_id: Reactome:R-HSA-418594 title: G alpha (i) signalling events supporting_text: >- The classical signalling mechanism for G alpha (i) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase (Dessauer C W et al. 2002). statement: >- Demonstrates that PDYN-derived dynorphin peptides signal through Gi/o-coupled OPRK1 to inhibit adenylate cyclase. - id: pnoc_prepronociceptin_ligand label: PNOC prepronociceptin (nociceptin/orphanin FQ) ligand participant: selector_type: FAMILY family: preferred_term: Prepronociceptin subfamily term: id: PANTHER:PTHR11438:SF2 label: PREPRONOCICEPTIN representative_members: - preferred_term: PNOC term: id: UniProtKB:Q13519 label: Prepronociceptin evidence: - source_id: file:interpro/panther/PTHR11438/PTHR11438-review.yaml title: PTHR11438 PANTHER family review statement: >- PTHR11438 review confirms family-wide GO:0001515 (opioid peptide activity), GO:0038003, and GO:0031635 across SF3 (PENK), SF4 (PDYN), and SF2 (PNOC). function: preferred_term: opioid peptide activity term: id: GO:0001515 label: opioid peptide activity processes: - preferred_term: G protein-coupled opioid receptor signaling pathway term: id: GO:0038003 label: G protein-coupled opioid receptor signaling pathway - preferred_term: adenylate cyclase-inhibiting opioid receptor signaling pathway term: id: GO:0031635 label: adenylate cyclase-inhibiting opioid receptor signaling pathway locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Endogenous opioid-related neuropeptide precursor processed into the heptadecapeptide nociceptin (orphanin FQ, bearing an N-terminal Phe-Gly-Gly-Phe message motif), which selectively binds and activates the nociceptin opioid receptor OPRL1 (NOP) to initiate Gi/o-coupled adenylate cyclase-inhibiting signaling. evidence: - source_id: Reactome:R-HSA-418594 title: G alpha (i) signalling events supporting_text: >- The classical signalling mechanism for G alpha (i) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase (Dessauer C W et al. 2002). statement: >- Establishes that PNOC-derived nociceptin activates Gi/o-coupled OPRL1 to inhibit adenylate cyclase. - id: oprm1_mu_opioid_receptor label: OPRM1 mu-type opioid receptor participant: selector_type: FAMILY family: preferred_term: Mu-type opioid receptor subfamily term: id: PANTHER:PTHR24229:SF7 label: MU-TYPE OPIOID RECEPTOR representative_members: - preferred_term: OPRM1 term: id: UniProtKB:P35372 label: Mu-type opioid receptor evidence: - source_id: Reactome:R-HSA-374298 title: Opioid receptors bind opioid peptides supporting_text: >- The mu-opioid receptor (MOR) (Wang JB et al, 1994) possesses high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. statement: >- OPRM1 is the mu-type opioid GPCR coupled to Gi/o signaling. function: preferred_term: G protein-coupled opioid receptor activity term: id: GO:0004985 label: G protein-coupled opioid receptor activity processes: - preferred_term: G protein-coupled opioid receptor signaling pathway term: id: GO:0038003 label: G protein-coupled opioid receptor signaling pathway - preferred_term: adenylate cyclase-inhibiting opioid receptor signaling pathway term: id: GO:0031635 label: adenylate cyclase-inhibiting opioid receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Seven-transmembrane Gi/o-coupled mu-type opioid receptor activated by PENK-derived enkephalins and beta-endorphin to inhibit adenylate cyclase. evidence: - source_id: Reactome:R-HSA-374298 title: Opioid receptors bind opioid peptides supporting_text: >- The mu-opioid receptor (MOR) (Wang JB et al, 1994) possesses high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. statement: >- Establishes OPRM1 as a Gi/o-coupled opioid receptor inhibiting adenylate cyclase. - id: oprd1_delta_opioid_receptor label: OPRD1 delta-type opioid receptor participant: selector_type: FAMILY family: preferred_term: Delta-type opioid receptor subfamily term: id: PANTHER:PTHR24229:SF2 label: DELTA-TYPE OPIOID RECEPTOR representative_members: - preferred_term: OPRD1 term: id: UniProtKB:P41143 label: Delta-type opioid receptor evidence: - source_id: Reactome:R-HSA-374298 title: Opioid receptors bind opioid peptides supporting_text: >- Enkephalins are pentapeptides involved in regulating pain and nociception in the body. Their action is mediated through the delta-opioid receptor (DOR) (Knapp RJ et al, 1994). statement: >- OPRD1 is the delta-type opioid GPCR coupled to Gi/o signaling. function: preferred_term: G protein-coupled opioid receptor activity term: id: GO:0004985 label: G protein-coupled opioid receptor activity processes: - preferred_term: G protein-coupled opioid receptor signaling pathway term: id: GO:0038003 label: G protein-coupled opioid receptor signaling pathway - preferred_term: adenylate cyclase-inhibiting opioid receptor signaling pathway term: id: GO:0031635 label: adenylate cyclase-inhibiting opioid receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Seven-transmembrane Gi/o-coupled delta-type opioid receptor preferentially activated by PENK-derived Met- and Leu-enkephalins to inhibit adenylate cyclase. evidence: - source_id: Reactome:R-HSA-374298 title: Opioid receptors bind opioid peptides supporting_text: >- Enkephalins are pentapeptides involved in regulating pain and nociception in the body. Their action is mediated through the delta-opioid receptor (DOR) (Knapp RJ et al, 1994). statement: >- Establishes OPRD1 as a Gi/o-coupled opioid receptor inhibiting adenylate cyclase. - id: oprk1_kappa_opioid_receptor label: OPRK1 kappa-type opioid receptor participant: selector_type: FAMILY family: preferred_term: Kappa-type opioid receptor subfamily term: id: PANTHER:PTHR24229:SF1 label: KAPPA-TYPE OPIOID RECEPTOR representative_members: - preferred_term: OPRK1 term: id: UniProtKB:P41145 label: Kappa-type opioid receptor evidence: - source_id: PMID:9047294 title: NMR and structural model of dynorphin A (1-17) bound to dodecylphosphocholine micelles. supporting_text: >- Dynorphin A (1-17) (dynorphin) acts preferentially and with high affinity at the kappa-opioid receptor, for which it is the natural, endogenous ligand. statement: >- Establishes OPRK1 as the high-affinity kappa-opioid receptor for PDYN-derived dynorphin A. function: preferred_term: G protein-coupled opioid receptor activity term: id: GO:0004985 label: G protein-coupled opioid receptor activity processes: - preferred_term: G protein-coupled opioid receptor signaling pathway term: id: GO:0038003 label: G protein-coupled opioid receptor signaling pathway - preferred_term: adenylate cyclase-inhibiting opioid receptor signaling pathway term: id: GO:0031635 label: adenylate cyclase-inhibiting opioid receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Seven-transmembrane Gi/o-coupled kappa-type opioid receptor preferentially activated by PDYN-derived dynorphins to inhibit adenylate cyclase. evidence: - source_id: PMID:9047294 title: NMR and structural model of dynorphin A (1-17) bound to dodecylphosphocholine micelles. supporting_text: >- Dynorphin A (1-17) (dynorphin) acts preferentially and with high affinity at the kappa-opioid receptor, for which it is the natural, endogenous ligand. statement: >- Establishes OPRK1 as the physiological receptor for dynorphin A. - id: oprl1_nociceptin_receptor label: OPRL1 nociceptin opioid receptor (NOP) participant: selector_type: FAMILY family: preferred_term: Nociceptin receptor subfamily term: id: PANTHER:PTHR24229:SF11 label: NOCICEPTIN RECEPTOR representative_members: - preferred_term: OPRL1 term: id: UniProtKB:P41146 label: Nociceptin receptor evidence: - source_id: Reactome:R-HSA-111885 title: Opioid Signalling supporting_text: >- Opioids receptors are G-protein coupled receptors (GPCR). There are four classes of receptors: mu (MOR), kappa (KOR) and delta (DOR), and the nociceptin receptor (NOP). statement: >- OPRL1 is the nociceptin/orphanin FQ receptor coupled to Gi/o signaling. function: preferred_term: G protein-coupled opioid receptor activity term: id: GO:0004985 label: G protein-coupled opioid receptor activity processes: - preferred_term: G protein-coupled opioid receptor signaling pathway term: id: GO:0038003 label: G protein-coupled opioid receptor signaling pathway - preferred_term: adenylate cyclase-inhibiting opioid receptor signaling pathway term: id: GO:0031635 label: adenylate cyclase-inhibiting opioid receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Seven-transmembrane Gi/o-coupled nociceptin/orphanin FQ opioid receptor (NOP) selectively activated by PNOC-derived nociceptin to inhibit adenylate cyclase. evidence: - source_id: Reactome:R-HSA-111885 title: Opioid Signalling supporting_text: >- Opioids receptors are G-protein coupled receptors (GPCR). There are four classes of receptors: mu (MOR), kappa (KOR) and delta (DOR), and the nociceptin receptor (NOP). statement: >- Establishes OPRL1 as a Gi/o-coupled opioid-family receptor inhibiting adenylate cyclase. - order: 2 role: Gi/o activation and adenylate cyclase inhibition node: id: opioid_gi_adenylate_cyclase_inhibition label: Gi/o activation and adenylate cyclase inhibition downstream of opioid receptors module_type: REGULATORY_STEP description: >- Agonist-activated OPRM1, OPRD1, OPRK1, and OPRL1 catalyze GDP-to-GTP exchange on pertussis-toxin-sensitive inhibitory Gi/o alpha subunits (exemplified by GNAI1), which directly inhibit membrane-bound adenylate cyclases (exemplified by ADCY5) to lower intracellular cAMP levels. annotons: - id: gnai1_gi_alpha label: GNAI1 Gi alpha-1 subunit participant: selector_type: FAMILY family: preferred_term: Guanine nucleotide-binding protein G(i) subunit alpha-1 subfamily term: id: PANTHER:PTHR10218:SF359 label: GUANINE NUCLEOTIDE-BINDING PROTEIN G(I) SUBUNIT ALPHA-1 representative_members: - preferred_term: GNAI1 term: id: UniProtKB:P63096 label: Guanine nucleotide-binding protein G(i) subunit alpha-1 evidence: - source_id: Reactome:R-HSA-418594 title: G alpha (i) signalling events supporting_text: >- The classical signalling mechanism for G alpha (i) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase (Dessauer C W et al. 2002). statement: >- Activated Gi/o alpha subunits inhibit adenylate cyclase and cAMP-dependent signaling. function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: G protein-coupled opioid receptor signaling pathway term: id: GO:0038003 label: G protein-coupled opioid receptor signaling pathway - preferred_term: adenylate cyclase-inhibiting opioid receptor signaling pathway term: id: GO:0031635 label: adenylate cyclase-inhibiting opioid receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Inhibitory Gi alpha subunit activated by ligand-bound opioid receptors to inhibit adenylate cyclase. evidence: - source_id: Reactome:R-HSA-418594 title: G alpha (i) signalling events supporting_text: >- The classical signalling mechanism for G alpha (i) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase (Dessauer C W et al. 2002). statement: >- Establishes that activated Gi/o alpha subunits signal by inhibiting adenylate cyclase. - id: adcy5_adenylate_cyclase label: ADCY5 adenylate cyclase type 5 effector participant: selector_type: FAMILY family: preferred_term: Adenylate cyclase type 5 subfamily term: id: PANTHER:PTHR45627:SF7 label: ADENYLATE CYCLASE TYPE 5 representative_members: - preferred_term: ADCY5 term: id: UniProtKB:O95622 label: Adenylate cyclase type 5 evidence: - source_id: Reactome:R-HSA-418594 title: G alpha (i) signalling events supporting_text: >- The classical signalling mechanism for G alpha (i) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase (Dessauer C W et al. 2002). statement: >- GTP-bound Gi/o alpha subunits inhibit adenylate cyclase and cAMP-dependent signaling. function: preferred_term: adenylate cyclase activity term: id: GO:0004016 label: adenylate cyclase activity processes: - preferred_term: G protein-coupled opioid receptor signaling pathway term: id: GO:0038003 label: G protein-coupled opioid receptor signaling pathway - preferred_term: adenylate cyclase-inhibiting opioid receptor signaling pathway term: id: GO:0031635 label: adenylate cyclase-inhibiting opioid receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Membrane-bound adenylate cyclase effector inhibited by GTP-bound Gi/o alpha subunits downstream of opioid receptor activation. evidence: - source_id: Reactome:R-HSA-418594 title: G alpha (i) signalling events supporting_text: >- The classical signalling mechanism for G alpha (i) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase (Dessauer C W et al. 2002). statement: >- Demonstrates adenylate cyclase inhibition as the canonical effector step of activated Gi/o alpha subunits. connections: - source: opioid_receptor_engagement target: opioid_gi_adenylate_cyclase_inhibition connection_type: CAUSES description: >- Binding of PENK-, PDYN-, or PNOC-derived opioid peptides to OPRM1, OPRD1, OPRK1, or OPRL1 stabilizes the active receptor conformation that catalyzes GDP-to-GTP exchange on GNAI1 and inhibits ADCY5.