PDYN Curation Notes (Human Proenkephalin-B / Prodynorphin, UniProtKB:P01213)

Summary of Gene Function

• Gene symbol / ID: PDYN (UniProtKB:P01213, HGNC:8820)
• PANTHER family: PANTHER:PTHR11438:SF4 (PROENKEPHALIN-B, within PANTHER:PTHR11438 PROENKEPHALIN; root PAINT node PANTHER:PTN000153716, clade node PANTHER:PTN002606008).
• Preprohormone processing: Synthesized in striatonigral medium spiny neurons, hippocampal dentate gyrus granule cells (mossy fibers), hypothalamic magnocellular neurons, and spinal cord dorsal horn neurons as a 254-amino-acid polyprotein precursor (signal peptide residues 1-20) packaged into neuronal dense-core vesicles in axon terminals and dendrites PMID:10098940. Cleaved at dibasic and monobasic sites by prohormone convertases (PC1, PC2) and carboxypeptidase E into multiple bioactive opioid peptides bearing an N-terminal Leu-enkephalin (YGGFL) core followed by basic C-terminal address extensions:
• Alpha-neoendorphin (residues 175-184) and beta-neoendorphin (residues 175-183)
• Dynorphin A(1-17) (residues 207-223), Dynorphin A(1-13) (residues 207-219), and Dynorphin A(1-8) (residues 207-214)
• Leumorphin / Dynorphin B-29 (residues 226-254) and Dynorphin B / rimorphin (residues 226-238)
• Leu-enkephalin (YGGFL, cleaved from the N-termini of neoendorphin, dynorphin A, and dynorphin B).
• Signaling mechanism: Mature dynorphin and neoendorphin peptides function as secreted opioid neuropeptide hormones (GO:0001515 opioid peptide activity, child of GO:0005184 neuropeptide hormone activity and GO:0048018 receptor ligand activity) that act preferentially and with subnanomolar affinity as the natural endogenous ligands for the kappa-type opioid receptor (OPRK1 / KOR; and with lower selectivity OPRM1 and OPRD1) (GO:0031628 opioid receptor binding, GO:0038003 G protein-coupled opioid receptor signaling pathway) PMID:9047294. Agonist-bound OPRK1 couples to pertussis-toxin-sensitive inhibitory Gi/o heterotrimeric G proteins (GNAI1/GNAI2/GNAI3) to inhibit adenylate cyclase (GO:0031635 adenylate cyclase-inhibiting opioid receptor signaling pathway), open GIRK potassium channels, and inhibit voltage-gated Ca2+ channels, thereby suppressing presynaptic glutamate and dopamine release (GO:0007270 neuron-neuron synaptic transmission) and modulating pain perception (GO:0019233) and stress/aversion circuits [PMID:9047294, PMID:10098940, PMID:18384820, PMID:22437502, Reactome:R-HSA-374298].

Ligands in Signaling Pathways Assessment (Tranche 4C)

• Unlike PENK (which carries an IEA GO_REF:0000107 Ensembl Compara projection from mouse UniProtKB:P22005 for GO:0038003 G protein-coupled opioid receptor signaling pathway), human PDYN lacks both GO:0038003 (G protein-coupled opioid receptor signaling pathway) and GO:0031635 (adenylate cyclase-inhibiting opioid receptor signaling pathway) in GOA (Category A gap!), carrying only the parent GO:0007218 (neuropeptide signaling pathway, IBA from PTN000153716 and IEA).
• We ACCEPT both rows of GO:0007218 (neuropeptide signaling pathway, IBA/IEA) alongside the specific child pathways, and add NEW annotations for GO:0038003 (IDA, backed by PMID:9047294) and GO:0031635 (IC, backed by PMID:18384820, PMID:22437502, and PMID:9047294, inferred from pre-existing GO:0001515, GO:0031628, and GO:0007218 together with the newly added GO:0038003 row), linking PDYN to MODULE:opioid_receptor_signaling.