K9IWC0 is the C-type natriuretic peptide (CNP/NPPC) precursor of the common vampire bat, expressed at high levels in the principal submaxillary salivary gland. The 119-residue preprohormone has a signal peptide (residues 1-23), a long disordered pro-region, and a C-terminal 17-residue disulfide ring (CFGQKLDRIGALSGLGC) that constitutes the mature bioactive peptide. Unlike the cardiac hormones ANP and BNP, CNP is not a circulating endocrine hormone: it is a locally acting paracrine peptide, produced chiefly by vascular endothelium in mammals, that potently relaxes arterial and venous smooth muscle. It signals by binding the membrane guanylyl cyclase receptor NPR2 (GC-B), whose cytoplasmic guanylate cyclase domain generates cGMP, and is removed by the clearance receptor NPR3. In the vampire bat the peptide is a salivary product rather than a cardiovascular one, and it is understood as one of the vasodilators - alongside PACAP - that keep blood flowing at the bite site during a blood meal.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006182 cGMP biosynthetic process | IEA GO_REF:0000118 | ACCEPT | Summary: Natriuretic peptides act by binding a membrane guanylyl cyclase receptor whose cytoplasmic catalytic domain converts GTP to cGMP, so the peptide drives cGMP production in the responding cell. The term is correct, but the receptor is NPR2 (GC-B), not NPR1 as stated in the UniProt FUNCTION block: that sentence is BNP/ANP biology carried over with the incorrect paralogue name. Reason: Correct for a natriuretic peptide of any subtype. Accepted with the receptor identity corrected in the summary rather than modified, since the GO term itself does not name a receptor. Supporting Evidence: PMID:23411029 These receptors contain at the C-terminus a guanylate cyclase functional domain that generates the second messenger cGMP for signaling purposes PMID:23411029 CNP interacts with two subtypes of natriuretic peptide receptor, namely NPR-B and NPR-C. file:DESRO/K9IWC0/K9IWC0-deep-research-falcon.md is the cognate receptor for CNP but can contribute to cGMP signaling in some contexts |
| GO:0007168 receptor guanylyl cyclase signaling pathway | IEA GO_REF:0000118 | ACCEPT | Summary: CNP is the ligand of the receptor guanylyl cyclase NPR2 (GC-B). The pathway term is exactly right for this peptide and is independent of the NPPB/NPPC naming problem, since both subtypes signal through a receptor guanylyl cyclase. Reason: Directly supported. This is the signalling pathway the peptide initiates. Supporting Evidence: PMID:23411029 CNP interacts with two subtypes of natriuretic peptide receptor, namely NPR-B and NPR-C. PMID:23411029 These receptors contain at the C-terminus a guanylate cyclase functional domain that generates the second messenger cGMP for signaling purposes |
| GO:0005179 hormone activity | IEA GO_REF:0000120 | ACCEPT | Summary: Hormone activity is retained. The human orthologue NPPC carries this term from experimental evidence and by phylogenetic inference, so the term is appropriate at the family level. The caveat worth recording is that CNP behaves as a local paracrine regulator rather than a circulating endocrine hormone, and that in this species the peptide is a salivary secretion acting on host vasculature rather than a cardiovascular hormone acting on the bat's own tissues. Reason: Consistent with the curated annotation of the human NPPC orthologue. The paracrine and salivary caveats are recorded here and in the knowledge gaps rather than by weakening the term. Supporting Evidence: PMID:23411029 CNP is a potent relaxant of arterial and venous smooth muscle in most mammalian species in vitro and is thought to act locally as a paracrine/autoregulator |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: The precursor carries a signal peptide (1-23) with a cleaved 24-119 chain and UniProt records the subcellular location as Secreted. For a small soluble secreted peptide, extracellular region is the appropriate location term. Reason: A secreted soluble peptide hormone; extracellular region is correct. GO has since obsoleted GO:0005615 extracellular space, the replacement previously proposed here, and merged it into GO:0005576 (replaced_by), so this term is now the correct location term. Supporting Evidence: file:DESRO/K9IWC0/K9IWC0-uniprot.txt SUBCELLULAR LOCATION: Secreted file:DESRO/K9IWC0/K9IWC0-uniprot.txt SIGNAL 1..23 |
| GO:0097746 blood vessel diameter maintenance | IEA GO_REF:0000043 | MODIFY | Summary: This keyword-derived term (from the Vasoactive keyword) is correct but directionless: it covers both constriction and dilation. CNP is a potent relaxant of arterial and venous smooth muscle, and the Vampirome authors state directly that the function of the bat salivary CNP is related to vasodilation. An earlier version of this review marked the term as over-annotated; the better call is to make it specific. GO:0042311 vasodilation is a direct child of GO:0097746. Reason: Replace the direction-neutral parent with the specific child GO:0042311 vasodilation, which is what CNP actually does and what the salivary peptide is inferred to do at the bite site. Proposed replacements: vasodilation Supporting Evidence: PMID:23411029 CNP is a potent relaxant of arterial and venous smooth muscle in most mammalian species in vitro and is thought to act locally as a paracrine/autoregulator PMID:23411029 The function of bat CNP is related to vasodilation. file:DESRO/K9IWC0/K9IWC0-uniprot.txt Vasoactive {ECO:0000256|ARBA:ARBA00022858, ECO:0000256|RuleBase:RU003686}. |
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Download this section (compressed HTML)Q: Is the CNP transcribed in the vampire bat principal submaxillary gland actually secreted into saliva and delivered to the host, and does it relax host vessels at physiologically achievable concentrations?
Suggested experts: Ivo M. B. Francischetti, José M. C. Ribeiro
Q: Does salivary CNP act in concert with the other vampire bat salivary vasodilator PACAP, and if so are their effects additive or do they target different vessel beds at the bite site?
Q: Has the vampire bat CNP ring sequence been under selection relative to other bats, in the way vampire bat lysozyme has, which would indicate recruitment of an endothelial peptide into a salivary role?
Experiment: Synthesise the mature 17-residue ring peptide CFGQKLDRIGALSGLGC and assay relaxation of pre-constricted arterial rings from a typical host species in a wire myograph, with and without the NPR2 antagonist P19; in parallel measure cGMP accumulation in cells expressing host NPR2 versus NPR1 to confirm receptor selectivity.
Hypothesis: Vampire bat salivary CNP is a functional vasodilator acting on host vasculature through NPR2.
Type: Myograph vasorelaxation with receptor-selective cGMP assay
Experiment: Collect saliva from feeding bats and run targeted parallel reaction monitoring mass spectrometry for the mature CNP ring peptide and for pro-region fragments, quantifying against a synthetic heavy-labelled standard.
Hypothesis: The peptide is present in expectorated saliva, not merely transcribed in the gland.
Type: Targeted quantitative proteomics
Experiment: Compare NPPC transcript abundance in submaxillary gland versus heart and aorta across Desmodus rotundus and non-sanguivorous phyllostomid bats by RT-qPCR, and test the coding sequence for lineage-specific selection.
Hypothesis: Salivary CNP expression is a derived feature of sanguivorous bats rather than the general endothelial expression seen in other mammals.
Type: Comparative expression profiling and selection analysis
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