Secreted vertebrate opioid neuropeptide polyprotein precursor (Proenkephalin-B / Prodynorphin) synthesized in striatonigral medium spiny neurons, hippocampal dentate gyrus granule cells (mossy fibers), hypothalamic magnocellular neurons, and spinal cord dorsal horn interneurons. Packaged into the lumen of neuronal dense-core vesicles and proteolytically cleaved at paired basic sites by prohormone convertases PC1/PC2 (PCSK1/PCSK2) and carboxypeptidase E (CPE) into multiple bioactive opioid peptides sharing an N-terminal Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu) message sequence with basic C-terminal address extensions: dynorphin A(1-17), dynorphin A(1-8), dynorphin B (rimorphin), alpha-neoendorphin, beta-neoendorphin, leumorphin, and Leu-enkephalin. Following activity-dependent exocytosis into the extracellular region, mature dynorphin peptides act as high-affinity endogenous opioid peptide agonists preferentially at the Gi/o-coupled kappa-opioid receptor (OPRK1, KOR) β and with lower selectivity at mu (OPRM1) and delta (OPRD1) opioid receptors β to initiate the G protein-coupled opioid receptor signaling pathway and its canonical adenylate cyclase-inhibiting opioid receptor signaling pathway, suppressing presynaptic voltage-gated calcium channels, activating GIRK potassium channels, and modulating synaptic transmission, nociception, and stress/aversion circuits.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001515 opioid peptide activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function of mature dynorphin and neoendorphin peptides cleaved from PDYN, transferred by phylogenetic inference from the vertebrate opioid precursor family root. Reason: PDYN is cleaved into dynorphin A(1-17), dynorphin A(1-8), dynorphin B (rimorphin), alpha- and beta-neoendorphin, and Leu-enkephalin, which are the canonical endogenous opioid peptide agonists for the kappa-opioid receptor OPRK1 (PMID:9047294, Reactome:R-HSA-374298). Supporting Evidence: PMID:9047294 Dynorphin A (1-17) (dynorphin) acts preferentially and with high affinity at the kappa-opioid receptor, for which it is the natural, endogenous ligand. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Uninformative bare protein binding annotation from high-throughput BioPlex affinity purification-mass spectrometry (LCN1, P31025). Reason: Per the protein-binding policy, bare GO:0005515 from high-throughput AP-MS screens (PMID:28514442) is uninformative and is removed in favor of specific opioid peptide activity (GO:0001515) and opioid receptor binding (GO:0031628). |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Uninformative bare protein binding annotation from high-throughput BioPlex affinity purification-mass spectrometry (LCN1, P31025). Reason: Per the protein-binding policy, bare GO:0005515 from high-throughput AP-MS screens (PMID:33961781) is uninformative and is removed in favor of specific opioid peptide activity (GO:0001515) and opioid receptor binding (GO:0031628). |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: Core extracellular localization of secreted dynorphin and neoendorphin peptides. Reason: PDYN carries an N-terminal signal peptide (residues 1-20) and its cleaved opioid peptides are secreted into the extracellular space via regulated exocytosis. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-112042 | ACCEPT | Summary: Core extracellular localization of secreted opioid peptides binding mu-opioid receptor in Reactome. Reason: Mature peptides cleaved from PDYN act in the extracellular space at cell-surface opioid receptors (Reactome:R-HSA-112042). |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-112271 | ACCEPT | Summary: Core extracellular localization of secreted opioid peptides in the liganded opioid receptor:G-protein complex in Reactome. Reason: Mature peptides cleaved from PDYN remain bound to the extracellular orthosteric pocket of opioid receptors during G-protein dissociation (Reactome:R-HSA-112271). |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-167408 | ACCEPT | Summary: Core extracellular localization of secreted opioid peptides in Reactome opioid receptor signaling reactions. Reason: Mature dynorphin/neoendorphin peptides act in the extracellular space (Reactome:R-HSA-167408). |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-167419 | ACCEPT | Summary: Core extracellular localization of secreted opioid peptides in Reactome opioid receptor signaling reactions. Reason: Mature dynorphin/neoendorphin peptides act in the extracellular space (Reactome:R-HSA-167419). |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-167427 | ACCEPT | Summary: Core extracellular localization of secreted opioid peptides dissociating from opioid receptors in Reactome. Reason: Mature dynorphin/neoendorphin peptides act in the extracellular space (Reactome:R-HSA-167427). |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-167429 | ACCEPT | Summary: Core extracellular localization of secreted opioid peptides in Reactome opioid receptor signaling reactions. Reason: Mature dynorphin/neoendorphin peptides act in the extracellular space (Reactome:R-HSA-167429). |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-374298 | ACCEPT | Summary: Core extracellular localization of secreted opioid peptides binding opioid receptors in Reactome. Reason: Mature dynorphin and neoendorphin peptides bind opioid receptors in the extracellular region (Reactome:R-HSA-374298). |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-380073 | ACCEPT | Summary: Core extracellular localization of secreted opioid peptides in Gi-activating GPCR GEF reactions in Reactome. Reason: Mature dynorphin and neoendorphin peptides remain in the extracellular orthosteric pocket of Gi-coupled opioid receptors during G-protein activation (Reactome:R-HSA-380073). |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-749454 | ACCEPT | Summary: Core extracellular localization of secreted opioid peptides in Reactome Gi complex dissociation. Reason: Mature dynorphin and neoendorphin peptides act in the extracellular space (Reactome:R-HSA-749454). |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-749456 | ACCEPT | Summary: Core extracellular localization of secreted opioid peptides in Reactome Gi-activating GPCR reactions. Reason: Mature dynorphin and neoendorphin peptides act in the extracellular space (Reactome:R-HSA-749456). |
| GO:0005886 plasma membrane | IDA PMID:9047294 NMR and structural model of dynorphin A (1-17) bound to dode... | KEEP AS NON CORE | Summary: Reflects NMR structural characterization of dynorphin A(1-17) Partitioning into membrane-mimetic micelles prior to engaging the kappa-opioid receptor at the plasma membrane. Reason: Tessmer et al. (PMID:9047294) showed that dynorphin A(1-17) forms an amphipathic alpha-helix upon associating with membrane phospholipids, facilitating 2D membrane-assisted capture by the kappa-opioid receptor; retained as non-core relative to its primary localization in neuronal dense-core vesicles (GO:0099013) and the extracellular region (GO:0005576). Supporting Evidence: PMID:9047294 Dynorphin A (1-17) (dynorphin) acts preferentially and with high affinity at the kappa-opioid receptor, for which it is the natural, endogenous ligand. |
| GO:0007218 neuropeptide signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Core neuropeptide signaling role of mature dynorphin and neoendorphin peptides cleaved from PDYN. Reason: Mature dynorphin and neoendorphin peptides cleaved from PDYN are secreted neuropeptides that activate G protein-coupled opioid receptors (OPRK1, OPRM1, OPRD1; PMID:9047294, Reactome:R-HSA-374298); retained alongside the specific child pathways GO:0038003 (G protein-coupled opioid receptor signaling pathway) and GO:0031635 (adenylate cyclase-inhibiting opioid receptor signaling pathway). Supporting Evidence: PMID:9047294 Dynorphin A (1-17) (dynorphin) acts preferentially and with high affinity at the kappa-opioid receptor, for which it is the natural, endogenous ligand. |
| GO:0007218 neuropeptide signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: Valid InterPro2GO mapping from the opioid neuropeptide precursor signature (IPR006024) consistent with the IBA row on GO:0007218. Reason: Consistent with the IBA row on GO:0007218; retained alongside the specific child pathways GO:0038003 and GO:0031635. Supporting Evidence: PMID:9047294 Dynorphin A (1-17) (dynorphin) acts preferentially and with high affinity at the kappa-opioid receptor, for which it is the natural, endogenous ligand. |
| GO:0019233 sensory perception of pain | IBA GO_REF:0000033 | ACCEPT | Summary: Valid phylogenetic annotation seeded from mouse Pdyn (MGI:105308) and Penk (MGI:104629), reflecting the established role of spinal and supraspinal dynorphin peptides in nociception and analgesia. Reason: Endogenous dynorphins released in the spinal cord dorsal horn and brain modulate pain transmission via kappa-opioid receptors. |
| GO:0031628 opioid receptor binding | IBA GO_REF:0000033 | ACCEPT | Summary: Valid phylogenetic annotation capturing direct binding of mature dynorphin and neoendorphin peptides to G protein-coupled opioid receptors (OPRK1, OPRM1, OPRD1). Reason: Mature dynorphin peptides directly bind the orthosteric pocket of the kappa-opioid receptor OPRK1 with subnanomolar affinity and also bind OPRM1 and OPRD1 (PMID:9047294, Reactome:R-HSA-374298). Supporting Evidence: PMID:9047294 Dynorphin A (1-17) (dynorphin) acts preferentially and with high affinity at the kappa-opioid receptor, for which it is the natural, endogenous ligand. |
| GO:0043025 neuronal cell body | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Valid PAINT annotation reflecting synthesis and vesicular packaging of prodynorphin in neuronal somata prior to axonal and dendritic transport. Reason: Prodynorphin is synthesized in neuronal cell bodies before trafficking in dense-core vesicles to synaptic terminals where mature dynorphin peptides are released. |
| GO:0098686 hippocampal mossy fiber to CA3 synapse | IDA PMID:10098940 Ultrastructural localization of dynorphin in the dentate gyr... | KEEP AS NON CORE | Summary: Direct immunoelectron microscopic localization of dynorphin A in human dentate gyrus mossy fiber terminals (PMID:10098940). Reason: Zhang and Houser (PMID:10098940) demonstrated abundant dynorphin A immunoreactivity in mossy fiber axon terminals of the human dentate gyrus; retained as a valid anatomical sub-location alongside the core dense-core vesicle (GO:0098992 / GO:0099013) and extracellular (GO:0005576) compartments. Supporting Evidence: PMID:10098940 In electron microscopic preparations, dynorphin A immunoreactivity was highly associated with dense core vesicles and was localized predominantly in axon terminals in the inner molecular layer of the dentate gyrus, although some dynorphin-labeled dense core vesicles were also observed in dendritic shafts and spines. |
| GO:0098992 neuronal dense core vesicle | IDA PMID:10098940 Ultrastructural localization of dynorphin in the dentate gyr... | ACCEPT | Summary: Direct immunoelectron microscopic demonstration that dynorphin A is stored in neuronal dense core vesicles in human hippocampal mossy fiber terminals and dendrites (PMID:10098940). Reason: Zhang and Houser (PMID:10098940) directly localized dynorphin A to neuronal dense-core vesicles in human dentate gyrus axon terminals, dendritic shafts, and spines by preembedding immunoperoxidase electron microscopy. Supporting Evidence: PMID:10098940 In electron microscopic preparations, dynorphin A immunoreactivity was highly associated with dense core vesicles and was localized predominantly in axon terminals in the inner molecular layer of the dentate gyrus, although some dynorphin-labeled dense core vesicles were also observed in dendritic shafts and spines. |
| GO:0099013 neuronal dense core vesicle lumen | IBA GO_REF:0000033 | ACCEPT | Summary: Core vesicular sub-compartment where prodynorphin is stored and processed into mature dynorphin and neoendorphin peptides prior to exocytosis. Reason: Consistent with human immunoelectron microscopy (PMID:10098940), prodynorphin and its cleaved opioid peptides reside within the lumen of neuronal dense-core vesicles. Supporting Evidence: PMID:10098940 In electron microscopic preparations, dynorphin A immunoreactivity was highly associated with dense core vesicles and was localized predominantly in axon terminals in the inner molecular layer of the dentate gyrus, although some dynorphin-labeled dense core vesicles were also observed in dendritic shafts and spines. |
| GO:0038003 G protein-coupled opioid receptor signaling pathway | IDA PMID:9047294 NMR and structural model of dynorphin A (1-17) bound to dode... | NEW | Summary: Mature dynorphin and neoendorphin peptides cleaved from PDYN act as the high-affinity endogenous agonists for the G protein-coupled kappa-opioid receptor OPRK1 (and also activate OPRM1 and OPRD1) to initiate the G protein-coupled opioid receptor signaling pathway. Reason: Dynorphin A(1-17) is the canonical high-affinity endogenous agonist of the kappa-opioid receptor OPRK1 (PMID:9047294), directly initiating the G protein-coupled opioid receptor signaling pathway (GO:0038003; compare the fellow opioid peptide precursor human PENK, which already carries GO:0038003 in GOA). Supporting Evidence: PMID:9047294 Dynorphin A (1-17) (dynorphin) acts preferentially and with high affinity at the kappa-opioid receptor, for which it is the natural, endogenous ligand. |
| GO:0031635 adenylate cyclase-inhibiting opioid receptor signaling pathway | IC PMID:18384820 Supersensitivity to mu-opioid receptor-mediated inhibition o... | NEW | Summary: Binding of mature PDYN-derived opioid peptides (dynorphin A, dynorphin B, alpha/beta-neoendorphin) to Gi/o-coupled kappa, mu, and delta opioid receptors activates pertussis-toxin-sensitive Galpha_i/o subunits that inhibit adenylate cyclase. Reason: Inferred from pre-existing PDYN annotations GO:0001515 (opioid peptide activity), GO:0031628 (opioid receptor binding), and GO:0007218 (neuropeptide signaling pathway), together with GO:0038003 (G protein-coupled opioid receptor signaling pathway, added as NEW IDA from PMID:9047294 in this review). All four vertebrate opioid receptors (OPRK1, OPRM1, OPRD1, OPRL1) couple to pertussis-toxin-sensitive heterotrimeric Gi/o proteins whose canonical effector mechanism is inhibition of adenylate cyclase (GO:0031635; PMID:18384820, PMID:22437502, PMID:9047294). Supporting Evidence: PMID:18384820 In control animals, the mu-opioid selective agonists, sufentanil and DAMGO, stimulated [35S]5'-(gamma-thio)-triphosphate ([35S]GTP gamma S) binding and inhibited forskolin-stimulated adenylyl cyclase activity, through a mechanism involving pertussis toxin (PTX) sensitive G alpha(i/o) subunits. PMID:22437502 The ΞΌOR couples predominantly to Gi, the inhibitory G protein for adenylyl cyclase. ΞΌOR signaling through Gi is responsible for its analgesic properties4. PMID:9047294 Dynorphin A (1-17) (dynorphin) acts preferentially and with high affinity at the kappa-opioid receptor, for which it is the natural, endogenous ligand. |
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Download this section (compressed HTML)Q: How do the distinct basic C-terminal address extensions of dynorphin A(1-17), dynorphin A(1-8), dynorphin B, and alpha/beta-neoendorphin differentially bias Gi/o subtype activation versus beta-arrestin-2 recruitment at human OPRK1?
Experiment: Measure biased Galpha_i1/2/3/oA/oB vs. beta-arrestin-2 recruitment across the full panel of endogenous PDYN cleavage products β dynorphin A(1-17), dynorphin A(1-8), dynorphin B, alpha-neoendorphin, beta-neoendorphin, and leumorphin β at human OPRK1, OPRM1, and OPRD1 in BRET dissociation assays.
Hypothesis: C-terminally shorter products (dynorphin A(1-8), alpha-neoendorphin) exhibit reduced beta-arrestin-2 recruitment relative to full-length dynorphin A(1-17) at OPRK1 while retaining full Gi/o-mediated adenylate cyclase inhibition.
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