Proenkephalin-A (PENK) encodes a 267-amino-acid preproprotein that is proteolytically processed by prohormone convertases (PCSK1, PCSK2) and carboxypeptidase E (CPE) within neuronal dense-core vesicles and adrenal chromaffin granules into multiple bioactive opioid and sensory peptides, including four copies of Met-enkephalin (YGGFM), one copy of Leu-enkephalin (YGGFL), the C-terminally extended opioid peptides Met-enkephalin-Arg-Phe (MEAP) and Met-enkephalin-Arg-Gly-Leu, and bovine adrenal medulla peptides (BAM-22P, BAM-18P, BAM-12P, and BAM8-22). Released into the extracellular synaptic and perivascular space, the N-terminal Tyr-Gly-Gly-Phe-Met/Leu motif of PENK-derived enkephalins and BAM-22P binds and activates Gi/o-coupled delta (OPRD1) and mu (OPRM1) opioid receptors to inhibit adenylate cyclase and modulate nociception and synaptic transmission, whereas the C-terminal region of BAM-22P (and its N-terminally truncated fragment BAM8-22) potently activates the Gq/11-coupled primate itch receptor MRGPRX1 to mediate non-histaminergic pruritus.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001515 opioid peptide activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function of PENK-derived Met-enkephalin, Leu-enkephalin, BAM-22P, and extended enkephalin peptides. Reason: Human proenkephalin-A is processed into six Met-enkephalin-containing peptides (including four copies of Met-enkephalin, MEAP, Met-enkephalin-Arg-Gly-Leu, and BAM peptides) and one copy of Leu-enkephalin that act as endogenous opioid peptide agonists at OPRD1 and OPRM1 (PMID:7057924). Supporting Evidence: PMID:7057924 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. |
| GO:0001649 osteoblast differentiation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-correlated orthology over-annotation from rat calvarial osteoblast differentiation studies. Reason: Transferred by Ensembl Compara orthology from rat Penk based on developmental stage-dependent Penk mRNA expression in differentiating calvarial osteoblasts; secreted enkephalin neuropeptides do not directly execute the osteoblast differentiation program. |
| GO:0001666 response to hypoxia | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-response over-annotation transferred from rat studies where Penk mRNA is induced by hypoxia. Reason: Transferred by Ensembl Compara orthology from rat Penk, reflecting transcriptional induction of Penk in carotid body, adrenal medulla, or brainstem during hypoxia rather than PENK directly executing a cellular hypoxia-response pathway. |
| GO:0005184 neuropeptide hormone activity | TAS PMID:7057924 Primary structure of the human Met- and Leu-enkephalin precu... | ACCEPT | Summary: Core molecular function of PENK-derived enkephalins and BAM peptides as secreted neuropeptide hormones. Reason: PENK-derived peptides are secreted from central/peripheral neurons and adrenal chromaffin cells as neuropeptide hormones (PMID:7057924, PMID:37591889). Supporting Evidence: PMID:7057924 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. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: Core subcellular and extracellular localization (extracellular region) of proenkephalin-A and its processed peptides. Reason: Proenkephalin-A is synthesized in neuronal cell bodies and adrenal chromaffin cells, packaged and processed in neuronal dense-core vesicles and chromaffin granules, transported to axon termini, and secreted into the extracellular space (GO_REF:0000044). |
| GO:0005576 extracellular region | ISS GO_REF:0000024 | ACCEPT | Summary: Core subcellular and extracellular localization (extracellular region) of proenkephalin-A and its processed peptides. Reason: Proenkephalin-A is synthesized in neuronal cell bodies and adrenal chromaffin cells, packaged and processed in neuronal dense-core vesicles and chromaffin granules, transported to axon termini, and secreted into the extracellular space (GO_REF:0000024). |
| GO:0005576 extracellular region | TAS PMID:36302898 Ligand recognition and allosteric modulation of the human MR... | ACCEPT | Summary: Core subcellular and extracellular localization (extracellular region) of proenkephalin-A and its processed peptides. Reason: Proenkephalin-A is synthesized in neuronal cell bodies and adrenal chromaffin cells, packaged and processed in neuronal dense-core vesicles and chromaffin granules, transported to axon termini, and secreted into the extracellular space (PMID:36302898). |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-374298 | ACCEPT | Summary: Core subcellular and extracellular localization (extracellular region) of proenkephalin-A and its processed peptides. Reason: Proenkephalin-A is synthesized in neuronal cell bodies and adrenal chromaffin cells, packaged and processed in neuronal dense-core vesicles and chromaffin granules, transported to axon termini, and secreted into the extracellular space (Reactome:R-HSA-374298). |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-380073 | ACCEPT | Summary: Core subcellular and extracellular localization (extracellular region) of proenkephalin-A and its processed peptides. Reason: Proenkephalin-A is synthesized in neuronal cell bodies and adrenal chromaffin cells, packaged and processed in neuronal dense-core vesicles and chromaffin granules, transported to axon termini, and secreted into the extracellular space (Reactome:R-HSA-380073). |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-749454 | ACCEPT | Summary: Core subcellular and extracellular localization (extracellular region) of proenkephalin-A and its processed peptides. Reason: Proenkephalin-A is synthesized in neuronal cell bodies and adrenal chromaffin cells, packaged and processed in neuronal dense-core vesicles and chromaffin granules, transported to axon termini, and secreted into the extracellular space (Reactome:R-HSA-749454). |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-749456 | ACCEPT | Summary: Core subcellular and extracellular localization (extracellular region) of proenkephalin-A and its processed peptides. Reason: Proenkephalin-A is synthesized in neuronal cell bodies and adrenal chromaffin cells, packaged and processed in neuronal dense-core vesicles and chromaffin granules, transported to axon termini, and secreted into the extracellular space (Reactome:R-HSA-749456). |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-8952289 | KEEP AS NON CORE | Summary: Early secretory pathway transit compartment where nascent proenkephalin-A is folded and phosphorylated by FAM20C before packaging into dense-core vesicles. Reason: Following signal peptide cleavage, proenkephalin-A transits through the endoplasmic reticulum lumen and Golgi apparatus (where it is phosphorylated on Ser residues by FAM20C; Reactome:R-HSA-8952289) prior to sorting into dense-core secretory granules; retained as a non-core biosynthetic transit compartment. |
| GO:0007165 signal transduction | TAS PMID:7057924 Primary structure of the human Met- and Leu-enkephalin precu... | MODIFY | Summary: Broad signal transduction annotation that should be refined to G protein-coupled opioid receptor signaling pathway. Reason: GO:0007165 (signal transduction) is true but too general; PENK-derived peptides specifically initiate GO:0038003 (G protein-coupled opioid receptor signaling pathway) and GO:0031635 (adenylate cyclase-inhibiting opioid receptor signaling pathway). |
| GO:0007218 neuropeptide signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process of PENK-derived enkephalins and BAM peptides in neuropeptide GPCR signaling. Reason: PENK-derived peptides act as endogenous neuropeptide agonists at opioid receptors (OPRD1, OPRM1) and MRGPRX1 (PMID:7057924, PMID:37591889). |
| GO:0007218 neuropeptide signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: Core biological process of PENK-derived enkephalins and BAM peptides in neuropeptide GPCR signaling. Reason: PENK-derived peptides act as endogenous neuropeptide agonists at opioid receptors (OPRD1, OPRM1) and MRGPRX1 (PMID:7057924, PMID:37591889). |
| GO:0009636 response to toxic substance | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-response over-annotation transferred from rat studies measuring Penk mRNA or enkephalin levels after neurotoxin or xenobiotic exposure. Reason: Transferred by Ensembl Compara orthology from rat Penk, where striatal or hippocampal Penk transcription changes after neurotoxin administration; PENK does not directly mediate cellular detoxification or toxicant response. |
| GO:0014009 glial cell proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Non-core paracrine effect of enkephalin signaling on astrocyte and glial proliferation in developing rodent brain. Reason: Transferred by Ensembl Compara orthology from rat Penk, reflecting paracrine modulation of glial cell proliferation by opioid peptides acting on glial opioid receptors; retained as a non-core downstream cellular outcome. |
| GO:0019226 transmission of nerve impulse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Non-core neurophysiological role of PENK-derived enkephalins in modulating neuronal excitability and impulse transmission. Reason: Transferred by Ensembl Compara orthology from mouse Penk, reflecting neuromodulatory control of action potential firing and synaptic impulse transmission via Gi/o-coupled OPRD1 and OPRM1; retained as non-core alongside the more specific synaptic signaling via neuropeptide (GO:0099538). |
| GO:0019233 sensory perception of pain | IBA GO_REF:0000033 | ACCEPT | Summary: Core physiological function of PENK-derived enkephalins in endogenous antinociception and pain modulation. Reason: Enkephalins released in the spinal dorsal horn and periaqueductal gray are primary endogenous mediators of pain perception and antinociception. |
| GO:0030424 axon | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neuronal axonal localization where dense-core vesicles containing PENK-derived enkephalins are transported to presynaptic terminals. Reason: Enkephalin-containing dense-core vesicles are transported along axons to axon terminals (GO:0043679) in striatopallidal, dorsal horn, and autonomic neurons; retained as non-core relative to the specific dense-core vesicle lumen (GO:0099013) and axon terminus (GO:0043679) compartments. |
| GO:0030425 dendrite | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Somatodendritic localization of enkephalin-containing dense-core vesicles in central neurons. Reason: Proenkephalin-derived peptides are also stored in dendritic dense-core vesicles for somatodendritic release in striatal and dorsal horn neurons; retained as non-core alongside neuronal dense-core vesicle lumen (GO:0099013). |
| GO:0031628 opioid receptor binding | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function of PENK-derived enkephalins in binding delta and mu opioid receptors. Reason: Met-enkephalin, Leu-enkephalin, MEAP, and BAM-22P bind directly to the orthosteric pocket of delta (OPRD1) and mu (OPRM1) opioid receptors via their conserved Tyr-Gly-Gly-Phe-Met/Leu pharmacophore. |
| GO:0032280 symmetric synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Localization of PENK-derived enkephalins at inhibitory GABAergic/enkephalinergic symmetric synapses. Reason: Co-packaged with GABA in striatopallidal medium spiny neurons and spinal dorsal horn interneurons that form symmetric (Gray's type II) synapses; retained as a non-core anatomical sub-compartment. |
| GO:0032355 response to estradiol | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-response over-annotation transferred from rat studies showing estrogen-regulated Penk transcription in ventromedial hypothalamus. Reason: Transferred by Ensembl Compara orthology from rat Penk, whose promoter contains estrogen-responsive elements driving transcriptional induction in the ventromedial hypothalamus after estradiol treatment; PENK is a transcriptional target rather than a mediator of the cellular estradiol response pathway. |
| GO:0032496 response to lipopolysaccharide | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-response over-annotation transferred from rat studies showing Penk mRNA induction following systemic LPS challenge. Reason: Transferred by Ensembl Compara orthology from rat Penk, reflecting inflammatory/stress-induced transcription of Penk in neuroendocrine and immune cells after lipopolysaccharide administration rather than direct participation in TLR4/LPS signaling. |
| GO:0034466 chromaffin granule lumen | IEA GO_REF:0000044 | ACCEPT | Summary: Core subcellular and extracellular localization (chromaffin granule lumen) of proenkephalin-A and its processed peptides. Reason: Proenkephalin-A is synthesized in neuronal cell bodies and adrenal chromaffin cells, packaged and processed in neuronal dense-core vesicles and chromaffin granules, transported to axon termini, and secreted into the extracellular space (GO_REF:0000044). |
| GO:0034592 synaptic vesicle lumen | IEA GO_REF:0000107 | ACCEPT | Summary: Core subcellular and extracellular localization (synaptic vesicle lumen) of proenkephalin-A and its processed peptides. Reason: Proenkephalin-A is synthesized in neuronal cell bodies and adrenal chromaffin cells, packaged and processed in neuronal dense-core vesicles and chromaffin granules, transported to axon termini, and secreted into the extracellular space (GO_REF:0000107). |
| GO:0034599 cellular response to oxidative stress | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-response over-annotation transferred from rat studies where Penk expression changes under oxidative stress. Reason: Transferred by Ensembl Compara orthology from rat Penk, reflecting AP-1/CRE-mediated transcriptional induction of Penk during oxidative stress rather than PENK directly executing an antioxidant or oxidative-stress response pathway. |
| GO:0035094 response to nicotine | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-response over-annotation transferred from rat studies measuring striatal and adrenal Penk mRNA induction after nicotine administration. Reason: Transferred by Ensembl Compara orthology from rat Penk, reflecting nicotinic acetylcholine receptor-driven transcriptional induction of Penk in chromaffin cells and striatal neurons after nicotine exposure rather than direct participation in nicotinic receptor signaling. |
| GO:0035641 locomotory exploration behavior | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream organismal behavioral phenotype reflecting striatopallidal enkephalinergic modulation of open-field exploratory locomotion. Reason: Enkephalin signaling from indirect-pathway D2/Penk medium spiny neurons in the striatum modulates basal ganglia motor output and exploratory locomotion in rodents; retained as a non-core organismal behavioral outcome downstream of opioid receptor signaling. |
| GO:0035902 response to immobilization stress | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-response over-annotation transferred from rat studies showing hypothalamic and adrenal Penk mRNA upregulation after immobilization stress. Reason: Transferred by Ensembl Compara orthology from rat Penk, reflecting stress-induced transcriptional upregulation of Penk mRNA in the paraventricular hypothalamus and adrenal medulla following restraint/immobilization stress. |
| GO:0038003 G protein-coupled opioid receptor signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Core biological process of PENK-derived enkephalins in initiating G protein-coupled opioid receptor signaling. Reason: Met-enkephalin, Leu-enkephalin, and extended PENK opioid peptides bind and activate OPRD1 and OPRM1 to initiate Gi/o-coupled opioid receptor signaling. |
| GO:0042756 drinking behavior | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream organismal behavioral role of central enkephalinergic circuits in modulating fluid intake and palatability-driven drinking behavior. Reason: Endogenous enkephalin signaling via central mu and delta opioid receptors in hypothalamic and mesolimbic circuits modulates water and palatable fluid intake in rodents; retained as a non-core organismal behavioral phenotype. |
| GO:0043025 neuronal cell body | IBA GO_REF:0000033 | ACCEPT | Summary: Core subcellular and extracellular localization (neuronal cell body) of proenkephalin-A and its processed peptides. Reason: Proenkephalin-A is synthesized in neuronal cell bodies and adrenal chromaffin cells, packaged and processed in neuronal dense-core vesicles and chromaffin granules, transported to axon termini, and secreted into the extracellular space (GO_REF:0000033). |
| GO:0043025 neuronal cell body | IEA GO_REF:0000107 | ACCEPT | Summary: Core subcellular and extracellular localization (neuronal cell body) of proenkephalin-A and its processed peptides. Reason: Proenkephalin-A is synthesized in neuronal cell bodies and adrenal chromaffin cells, packaged and processed in neuronal dense-core vesicles and chromaffin granules, transported to axon termini, and secreted into the extracellular space (GO_REF:0000107). |
| GO:0043204 perikaryon | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Localization of proenkephalin-A in the neuronal perikaryon where the precursor is synthesized and packaged into Golgi-derived dense-core vesicles. Reason: Proenkephalin-A is translated in the rough ER and packaged into immature secretory granules within the neuronal perikaryon before axonal transport; retained as non-core alongside neuronal cell body (GO:0043025). |
| GO:0043679 axon terminus | IEA GO_REF:0000107 | ACCEPT | Summary: Core subcellular and extracellular localization (axon terminus) of proenkephalin-A and its processed peptides. Reason: Proenkephalin-A is synthesized in neuronal cell bodies and adrenal chromaffin cells, packaged and processed in neuronal dense-core vesicles and chromaffin granules, transported to axon termini, and secreted into the extracellular space (GO_REF:0000107). |
| GO:0045471 response to ethanol | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-response over-annotation transferred from rat studies measuring striatal and mesolimbic Penk mRNA changes after ethanol exposure. Reason: Transferred by Ensembl Compara orthology from rat Penk, reflecting ethanol-induced alterations in striatal and nucleus accumbens Penk transcription rather than PENK directly executing a cellular response to ethanol. |
| GO:0048018 receptor ligand activity | IDA PMID:37591889 Ligand recognition and G protein coupling of the human itch ... | MODIFY | Summary: Broad receptor ligand activity annotation that should be refined to opioid peptide activity and neuropeptide hormone activity. Reason: GO:0048018 (receptor ligand activity) is true of PENK cleavage products (including BAM8-22 at MRGPRX1 in PMID:37591889 and enkephalins at OPRD1/OPRM1) but less specific than GO:0001515 (opioid peptide activity) and GO:0005184 (neuropeptide hormone activity), which are already present on this gene. Proposed replacements: opioid peptide activity neuropeptide hormone activity Supporting Evidence: PMID:37591889 In particular, MRGPRX1, one of the itch receptors in humans, is able to respond to endogenous peptides, such as Ξ³2-melanocyte-stimulating hormone (Ξ³2-MSH)7, bovine adrenal medulla peptide (BAM) 8-228, and the antimalarial drug chloroquine (CQ)6, which has an intolerant itch side effect. |
| GO:0048018 receptor ligand activity | IEA GO_REF:0000107 | MODIFY | Summary: Broad receptor ligand activity annotation that should be refined to opioid peptide activity and neuropeptide hormone activity. Reason: GO:0048018 (receptor ligand activity) is true of PENK cleavage products (including BAM8-22 at MRGPRX1 in PMID:37591889 and enkephalins at OPRD1/OPRM1) but less specific than GO:0001515 (opioid peptide activity) and GO:0005184 (neuropeptide hormone activity), which are already present on this gene. Proposed replacements: opioid peptide activity neuropeptide hormone activity Supporting Evidence: PMID:37591889 In particular, MRGPRX1, one of the itch receptors in humans, is able to respond to endogenous peptides, such as Ξ³2-melanocyte-stimulating hormone (Ξ³2-MSH)7, bovine adrenal medulla peptide (BAM) 8-228, and the antimalarial drug chloroquine (CQ)6, which has an intolerant itch side effect. |
| GO:0048149 behavioral response to ethanol | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream organismal behavioral phenotype reflecting endogenous enkephalin/opioid receptor modulation of ethanol preference and reward in rodents. Reason: Endogenous enkephalin signaling in mesolimbic reward circuits modulates behavioral sensitivity and preference for ethanol via mu and delta opioid receptors; retained as a non-core organismal behavioral outcome downstream of opioid receptor signaling. |
| GO:0051592 response to calcium ion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-response over-annotation transferred from rat studies showing Ca2+/calmodulin-dependent transcriptional induction of the Penk promoter. Reason: Transferred by Ensembl Compara orthology from rat Penk, whose promoter contains CRE/AP-1 elements transcriptionally activated by depolarization-induced Ca2+ influx; PENK is a Ca2+-regulated target gene rather than a calcium sensor or mediator of the cellular response to calcium ion. |
| GO:0051867 general adaptation syndrome, behavioral process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream organismal behavioral role of endogenous enkephalin signaling in stress coping and adaptation. Reason: Enkephalinergic circuits in the amygdala, paraventricular hypothalamus, and periaqueductal gray buffer behavioral stress responses and anxiety-like behavior in rodents (including Penk-knockout phenotypes); retained as a non-core organismal behavioral outcome. |
| GO:0070852 cell body fiber | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neurite/cell body fiber localization of proenkephalin-derived peptides in transit between the soma and synaptic terminals. Reason: Reflects immunocytochemical detection of enkephalin-containing dense-core vesicles along proximal neuronal processes emerging from the cell body; retained as a non-core neuronal transit compartment. |
| GO:0071305 cellular response to vitamin D | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-response over-annotation transferred from rat studies where Penk mRNA levels change after 1,25-dihydroxyvitamin D3 treatment. Reason: Transferred by Ensembl Compara orthology from rat Penk based on vitamin D-induced modulation of Penk transcription in cultured cells rather than PENK directly participating in vitamin D receptor signaling. |
| GO:0071320 cellular response to cAMP | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-response over-annotation transferred from rat studies of the classic cAMP-responsive enhancer (CRE-1/CRE-2) in the Penk promoter. Reason: Transferred by Ensembl Compara orthology from rat Penk, whose promoter is a classic model of cAMP/PKA/CREB-inducible transcription; PENK is a transcriptional readout of cAMP rather than an intracellular mediator of the cellular response to cAMP. |
| GO:0071560 cellular response to transforming growth factor beta stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-response over-annotation transferred from rat studies where TGF-beta alters Penk mRNA expression. Reason: Transferred by Ensembl Compara orthology from rat Penk based on TGF-beta-induced regulation of Penk mRNA in cultured cells rather than PENK participating in the SMAD/TGF-beta signaling pathway. |
| GO:0071871 response to epinephrine | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-response over-annotation transferred from rat studies measuring chromaffin or neuronal Penk transcription after adrenergic stimulation. Reason: Transferred by Ensembl Compara orthology from rat Penk, reflecting catecholamine/cAMP-stimulated Penk transcription in adrenal medullary chromaffin cells rather than PENK mediating adrenergic receptor signaling. |
| GO:0098586 cellular response to virus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-response over-annotation transferred from rodent studies where viral infection or poly(I:C) alters Penk expression. Reason: Transferred by Ensembl Compara orthology from rat Penk based on transcriptional induction of Penk during viral or immune challenge rather than any direct antiviral function of enkephalin peptides. |
| GO:0099013 neuronal dense core vesicle lumen | IBA GO_REF:0000033 | ACCEPT | Summary: Core subcellular and extracellular localization (neuronal dense core vesicle lumen) of proenkephalin-A and its processed peptides. Reason: Proenkephalin-A is synthesized in neuronal cell bodies and adrenal chromaffin cells, packaged and processed in neuronal dense-core vesicles and chromaffin granules, transported to axon termini, and secreted into the extracellular space (GO_REF:0000033). |
| GO:0099013 neuronal dense core vesicle lumen | IEA GO_REF:0000107 | ACCEPT | Summary: Core subcellular and extracellular localization (neuronal dense core vesicle lumen) of proenkephalin-A and its processed peptides. Reason: Proenkephalin-A is synthesized in neuronal cell bodies and adrenal chromaffin cells, packaged and processed in neuronal dense-core vesicles and chromaffin granules, transported to axon termini, and secreted into the extracellular space (GO_REF:0000107). |
| GO:0099538 synaptic signaling via neuropeptide | IEA GO_REF:0000107 | ACCEPT | Summary: Core synaptic role of enkephalin peptides released from dense-core vesicles at central and peripheral synapses. Reason: Enkephalins are released from presynaptic terminals and somatodendritic dense-core vesicles to modulate synaptic transmission via pre- and postsynaptic opioid receptors. |
| GO:0160025 sensory perception of itch | IDA PMID:37591889 Ligand recognition and G protein coupling of the human itch ... | ACCEPT | Summary: Core physiological role of PENK-derived BAM8-22 peptide in activating human MRGPRX1 on dorsal root ganglion neurons to mediate itch sensation. Reason: BAM8-22, a proteolytic cleavage product of proenkephalin-A, is the canonical endogenous agonist of the primate itch receptor MRGPRX1 (PMID:37591889, PMID:36302898). Supporting Evidence: PMID:37591889 In particular, MRGPRX1, one of the itch receptors in humans, is able to respond to endogenous peptides, such as Ξ³2-melanocyte-stimulating hormone (Ξ³2-MSH)7, bovine adrenal medulla peptide (BAM) 8-228, and the antimalarial drug chloroquine (CQ)6, which has an intolerant itch side effect. |
| GO:1901652 response to peptide | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Expression-response over-annotation transferred from rat studies where peptide hormones alter Penk mRNA expression. Reason: Transferred by Ensembl Compara orthology from rat Penk, reflecting hormone- or neuropeptide-stimulated transcription of the Penk gene rather than PENK acting as an intracellular responder to peptide stimuli. |
| GO:2000987 positive regulation of behavioral fear response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream organismal behavioral phenotype reflecting amygdalar and periaqueductal gray enkephalin modulation of conditioned fear responses. Reason: Endogenous enkephalinergic neurons in the central and basolateral amygdala and periaqueductal gray modulate conditioned fear expression and extinction in rodents; retained as a non-core organismal behavioral outcome downstream of opioid receptor signaling. |
| GO:0031635 adenylate cyclase-inhibiting opioid receptor signaling pathway | IC PMID:18384820 Supersensitivity to mu-opioid receptor-mediated inhibition o... | NEW | Summary: PENK-derived Met-enkephalin, Leu-enkephalin, and extended opioid peptides directly initiate the adenylate cyclase-inhibiting opioid receptor signaling pathway via Gi/o-coupled OPRD1 and OPRM1. Reason: Met-enkephalin and Leu-enkephalin cleaved from proenkephalin-A (PMID:7057924) are the prototypical endogenous agonists of Gi/o-coupled delta (OPRD1) and mu (OPRM1) opioid receptors, which couple to pertussis-toxin-sensitive Galpha(i/o) subunits to inhibit forskolin-stimulated adenylyl cyclase activity (PMID:18384820, PMID:22437502). Inferred from GO:0001515 (opioid peptide activity), GO:0031628 (opioid receptor binding), and GO:0038003 (G protein-coupled opioid receptor signaling pathway). 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:7057924 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. |
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Download this section (compressed HTML)Q: Which tissue-specific aminopeptidases or endopeptidases convert full-length BAM-22P (a dual opioid receptor and MRGPRX1 agonist) into BAM8-22 (a selective MRGPRX1 pruritogen lacking the N-terminal opioid message) in human skin and dorsal root ganglia?
Suggested experts: Xinzhong Dong, Bryan L. Roth, Lakshmi A. Devi
Experiment: Perform targeted LC-MS/MS peptidomics and protease-inhibitor profiling on human skin interstitial fluid and cultured primary human keratinocytes/sensory neurons to quantify the ratio of BAM-22P to BAM8-22.
Hypothesis: Differential proteolytic processing of BAM-22P in inflamed human skin shifts the balance from N-terminal OPRM1/OPRD1 analgesia to C-terminal MRGPRX1 pruritus.
Type: TargetedLC-MS/MS peptidomics and GPCR signaling assay
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