PENK Curation Notes (Human Proenkephalin-A, UniProtKB:P01210)

Summary of Gene Function

• Gene symbol / ID: PENK (UniProtKB:P01210, HGNC:8831)
• PANTHER family: PANTHER:PTHR11438:SF3 (PROENKEPHALIN-A, within PANTHER:PTHR11438 PROENKEPHALIN; root PAINT node PANTHER:PTN000153716, clade node PANTHER:PTN002606001).
• Preprohormone processing: Synthesized in striatal medium spiny neurons, spinal cord dorsal horn interneurons, peripheral sensory/enteric neurons, and adrenal medullary chromaffin cells as a 267-amino-acid polyprotein precursor (signal peptide residues 1-24) packaged into the lumen of neuronal dense-core vesicles (GO:0099013) PMID:7057924. Cleaved at flanking dibasic sites by prohormone convertases (PC1/PCSK1, PC2/PCSK2) and carboxypeptidase E to yield:
• Four copies of Met-enkephalin (YGGFM, residues 100-104, 107-111, 136-140, 210-214)
• One copy of Leu-enkephalin (YGGFL, residues 230-234)
• One copy of the octapeptide Met-enkephalin-Arg-Gly-Leu (YGGFMRGL, residues 186-193)
• One copy of the heptapeptide Met-enkephalin-Arg-Phe (YGGFMRF, residues 261-267)
• Larger intermediate peptides including peptide E, BAM-18, BAM-22P, and BAM8-22 (which additionally activates the sensory neuron GPCR MRGPRX1 via Gq) [PMID:7057924, PMID:36302898].
• Signaling mechanism: Mature enkephalin peptides act as endogenous opioid peptide hormones/neuropeptides (GO:0001515 opioid peptide activity, child of GO:0005184 neuropeptide hormone activity and GO:0048018 receptor ligand activity) that bind and activate the delta-type (OPRD1) and mu-type (OPRM1) opioid receptors (GO:0031628 opioid receptor binding, GO:0038003 G protein-coupled opioid receptor signaling pathway) [PMID:7057924, Reactome:R-HSA-374298]. Agonist-bound OPRD1 and OPRM1 couple to pertussis-toxin-sensitive inhibitory Gi/o heterotrimeric G proteins (GNAI1/GNAI2/GNAI3/GNAO1) to inhibit adenylate cyclase (GO:0031635 adenylate cyclase-inhibiting opioid receptor signaling pathway), activate GIRK potassium channels, and inhibit presynaptic voltage-gated Ca2+ channels, suppressing nociceptive neurotransmission (GO:0019233 sensory perception of pain) [PMID:18384820, PMID:22437502].

Ligands in Signaling Pathways Assessment (Tranche 4C)

• Human PENK already carries GO:0038003 (G protein-coupled opioid receptor signaling pathway, IEA GO_REF:0000107 Ensembl Compara projection from mouse UniProtKB:P22005) and GO:0001515 (opioid peptide activity, IBA from PTN000153716), so GO:0038003 passes the ligand check in human, mouse, and rat (though zebrafish penka and penkb lack GO:0038003 because PAINT PTN000153716 only places GO:0007218 neuropeptide signaling pathway).
• However, on the canonical Gi/o effector child pathway GO:0031635 (adenylate cyclase-inhibiting opioid receptor signaling pathway), PENK is missing in human, mouse, and rat (Category B gap; only OPRK1 is annotated).
• We ACCEPT GO:0007218 (neuropeptide signaling pathway, IBA/IEA) and GO:0099538 (synaptic signaling via neuropeptide, IEA GO_REF:0000107), MODIFY the broad signaling row GO:0007165 (signal transduction, TAS PMID:7057924) to GO:0038003 (G protein-coupled opioid receptor signaling pathway) and GO:0031635 (adenylate cyclase-inhibiting opioid receptor signaling pathway), MODIFY GO:0048018 (receptor ligand activity, IDA PMID:37591889 and IEA GO_REF:0000107) to {GO:0001515, GO:0005184}, and add a NEW (IC) annotation for GO:0031635 backed by PMID:18384820 and PMID:22437502 (inferred from GO:0001515, GO:0031628, and GO:0038003), linking PENK to MODULE:opioid_receptor_signaling.
• Note on PMID:15538397 (GO:0006915 apoptotic process, GO:0030262 apoptotic nuclear changes, GO:0005634 nucleus): PMID:15538397 characterizes a non-secreted nuclear isoform of proenkephalin in stressed/tumor cells that sensitizes cells to apoptosis; we keep GO:0005634 as KEEP_AS_NON_CORE and mark the downstream apoptosis phenotype rows as KEEP_AS_NON_CORE.