EDN1 Curation Notes (Human Endothelin-1, UniProtKB:P05305)

Summary of Gene Function

• Gene symbol / ID: EDN1 (UniProtKB:P05305, HGNC:3176)
• PANTHER family: PANTHER:PTHR13874:SF10 (ENDOTHELIN-1, within PANTHER:PTHR13874 ENDOTHELIN; root PAINT node PANTHER:PTN000356323, clade node PANTHER:PTN002676936).
• Preprohormone processing: Synthesized primarily by vascular endothelial cells as a 212-amino-acid preproendothelin-1 (signal peptide residues 1-17). Cleaved at dibasic sites by furin-like proprotein convertases to yield the inactive 38-amino-acid intermediate big endothelin-1 (residues 53-90), which is then specifically cleaved at the Trp21-Val22 bond (residues 73-74) by endothelin-converting enzymes (ECE1, ECE2) to release the mature bioactive 21-residue bicyclic peptide Endothelin-1 (ET-1, residues 53-73), stabilized by two intramolecular disulfide bonds (Cys53-Cys67 and Cys55-Cys63) [PMID:2649896, PMID:1917960].
• Signaling mechanism: Mature ET-1 acts as a potent paracrine/autocrine peptide hormone (GO:0005179 hormone activity, child of GO:0048018 receptor ligand activity) that binds with subnanomolar affinity to both the ET-1/ET-2-selective Endothelin-1 receptor (EDNRA / ETA, GO:0031707 endothelin A receptor binding) on vascular smooth muscle cells and the nonselective Endothelin B receptor (EDNRB / ETB, GO:0031708 endothelin B receptor binding) on endothelial and smooth muscle cells [PMID:1713452, PMID:8982507, Reactome:R-HSA-388560]. Agonist-bound EDNRA and EDNRB couple primarily to heterotrimeric Gq/11 proteins (GNAQ/GNA11) to stimulate phospholipase C-beta (PLCB1/PLCB4), generating inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) and mobilizing intracellular Ca2+ (GO:0086100 endothelin receptor signaling pathway and GO:0160135 phospholipase C-activating endothelin receptor signaling pathway) PMID:1917960.
• Physiological and developmental roles: Potent vasoconstrictor and positive regulator of arterial and venous smooth muscle contraction (GO:0014826, GO:0045987) that maintains systemic arterial blood pressure (GO:0003100) [PMID:2649896, PMID:8982507]. During embryogenesis, EDN1 signaling through EDNRA on cranial neural crest cells is essential for first and second pharyngeal arch patterning (GO:0060021 roof of mouth development, GO:0060037 pharyngeal system development, GO:0048706 embryonic skeletal system development); pathogenic EDN1 variants cause auriculocondylar syndrome 3 and isolated question-mark ears PMID:24290376.

Ligands in Signaling Pathways Assessment (Tranche 4C)

• In human GOA, EDN1 carries GO:0086100 (endothelin receptor signaling pathway, IDA PMID:16820593 and PMID:9492062, IMP PMID:19086031, and IEA GO_REF:0000107) and GO:0005179 (hormone activity, IBA GO_REF:0000033 and IDA PMID:10770212 and PMID:2649896), so GO:0086100 passes the ligand check in human, mouse, and rat (though zebrafish edn1 lacks GO:0086100).
• However, on the specific child pathway GO:0160135 (phospholipase C-activating endothelin receptor signaling pathway), EDN1 is missing (Category B gap), even though PMID:1917960 directly demonstrated that 10 nM human ET-1 (and ET-2 and ET-3) stimulates phospholipase C to increase IP3 mass and mobilize intracellular Ca2+ in human cells. We therefore propose NEW (IC) for GO:0160135 (phospholipase C-activating endothelin receptor signaling pathway) backed by PMID:1917960 (inferred from GO:0031707, GO:0031708, and GO:0086100) and link EDN1 to MODULE:endothelin_receptor_signaling.
• For the broader/mis-signed signaling terms GO:0007166 (cell surface receptor signaling pathway, IDA PMID:1713452), GO:0007186 (G protein-coupled receptor signaling pathway, IDA PMID:17078114), GO:0007267 (cell-cell signaling, IDA PMID:12379507), GO:0023019 (signal transduction involved in regulation of gene expression, IDA PMID:16820593), GO:0035556 (intracellular signal transduction, IEA GO_REF:0000107), and GO:0160195 (negative regulation of phospholipase C/protein kinase C signal transduction, IDA PMID:16820593), we use MODIFY to GO:0086100 (endothelin receptor signaling pathway) and GO:0160135 (phospholipase C-activating endothelin receptor signaling pathway); and for GO:0005102 (signaling receptor binding, IEA GO_REF:0000107) and GO:0048018 (receptor ligand activity, IEA GO_REF:0000107), we use MODIFY to {GO:0005179, GO:0031707, GO:0031708}.