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 |
MODIFY |
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 the specific child term is the better fit.
Reason: Use GO:0005615 extracellular space, which is the appropriate granularity for a secreted soluble peptide hormone.
Proposed replacements:
extracellular space
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}.
|
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
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Plan status update and target verification
- Identity confirmed: UniProt K9IWC0 corresponds to a natriuretic peptide B precursor (BNP prohormone) annotated in Desmodus rotundus (vampire bat), belonging to the natriuretic peptide family with the conserved natriuretic peptide domain (IPR000663; PF00212). BNP/NPPB biology in mammals is well defined; therefore, functional annotation for K9IWC0 can be inferred from conserved domain/family knowledge and cross-mammalian literature. No conflicting gene symbol usage was identified. Species-specific, peer‑reviewed primary literature for BNP/NPPB in Desmodus rotundus was not found in our curated 2023–2024 evidence set; conclusions for this bat protein are thus based on conserved features of the natriuretic peptide family in mammals, which are highly conserved and well reviewed (see citations). Where bat-specific data are unavailable, this report explicitly infers function from family/domain conservation. (giovou2024theimpactof pages 5-7, corte2023thenatriureticpeptide pages 2-4, giovou2024theimpactof pages 19-20)
Comprehensive research report: K9IWC0 (NPPB/BNP precursor) in Desmodus rotundus
1) Key concepts and definitions with current understanding
- Gene/protein identity and family: NPPB encodes the B‑type natriuretic peptide (BNP), a cardiac endocrine hormone of the natriuretic peptide family (ANP/BNP/CNP), acting via particulate guanylyl cyclase receptors. BNP contains the hallmark 17‑residue disulfide-bonded ring within the natriuretic peptide domain responsible for receptor recognition. The K9IWC0 protein is the preprohormone (preproBNP) for BNP in vampire bat, sharing this conserved architecture. (Review synthesis) (corte2023thenatriureticpeptide pages 2-4, giovou2024theimpactof pages 5-7)
- Biosynthesis and processing: NPPB is translated as preproBNP (human canonical numbers: 134 aa), with an N‑terminal signal peptide removed to generate proBNP. ProBNP undergoes O‑glycosylation at sites near the convertase cleavage region, a modification that can modulate subsequent proteolysis. Endoproteolytic processing by the proprotein convertases corin and/or furin yields two principal products: the bioactive BNP1‑32 (humans) and the inactive N‑terminal fragment NT‑proBNP1‑76. Variable O‑glycosylation influences both physiological bioactivity and immunoassay detectability. (corte2023thenatriureticpeptide pages 2-4, giovou2024theimpactof pages 5-7, nyberg2023astateof pages 2-3)
- Receptors and signaling: BNP binds primarily to NPR1 (also GC‑A), a membrane guanylyl cyclase. Ligand binding stimulates intracellular cGMP generation, which activates downstream effectors including protein kinase G (PKG), selected phosphodiesterases, and cGMP-gated ion channels, producing vasorelaxation and anti‑remodeling effects. NPR2 (GC‑B) is the cognate receptor for CNP but can contribute to cGMP signaling in some contexts; NPR3 (clearance receptor) mediates endocytosis/lysosomal degradation and can also signal via Gi to inhibit adenylyl cyclase. (gallo2023natriureticpeptidesit pages 4-5, giovou2024theimpactof pages 5-7)
- Core physiological actions: Through NPR1-cGMP-PKG, BNP promotes natriuresis, diuresis, vasodilation, suppression of renin–angiotensin–aldosterone signaling, and anti‑hypertrophic/anti‑fibrotic actions in the heart. BNP’s relatively longer circulating half‑life versus ANP contributes to its biomarker utility. (gallo2023natriureticpeptidesit pages 1-2, giovou2024theimpactof pages 5-7)
- Localization: BNP is a secreted hormone produced by cardiomyocytes; under basal conditions, ANP/BNP are predominantly atrial, but with ventricular stress or disease, ventricular NPPB expression is strongly induced. (nyberg2023astateof pages 1-2, giovou2024theimpactof pages 5-7)
2) Recent developments and latest research (2023–2024 prioritized)
- NPR1 agonist antibody (REGN5381; translational advance): A 2024 Nature study reported a human genetic analysis linking NPR1 coding variants with blood pressure and heart-failure risk, then developed REGN5381, an allosteric agonist monoclonal antibody to NPR1. REGN5381 induces an active-like conformation and preferentially reduces venous pressures in animals; in healthy volunteers, it lowered venous pressures without clear natriuresis/diuresis, supporting a strategy for sustained venous decongestion. The paper also reiterates that ANP/BNP are activated by corin/furin and reports approximate circulating half-lives (ANP ~30 s; BNP ~6.4 min) in the experimental framework. URL: https://doi.org/10.1038/s41586-024-07903-1 (published 11 Sep 2024). (dunn2024agonistantibodyto pages 1-2)
- NPR3 (clearance receptor) as disease modifier: In a 2023 Science Advances study, genetic deletion of NPRC (NPR3) in diabetic mice attenuated cardiac fibrosis and improved remodeling/function, mechanistically linked to activation of PKA/PKG and inhibition of TGF‑β1/Smad signaling (via upregulation of TGIF1). These findings highlight therapeutic potential in modulating NP clearance/signaling balance. While this model focuses on diabetic cardiomyopathy, the mechanism is broadly relevant to BNP biology. (Full data summarized in our evidence context from the paper search; mechanistic conclusions tied here via review context.) (gallo2023natriureticpeptidesit pages 4-5)
- State of “natriuretic peptide deficiency”: An Endocrine Reviews 2023 perspective synthesizes evidence that many individuals exhibit partial NP deficiency—lower circulating NPs and/or reduced effective receptor-level bioactivity—particularly in obesity and type 2 diabetes. The review emphasizes the regulatory role of heterogeneous O‑glycosylation in propeptide maturation and assay interpretation, with implications for both diagnostics and pathophysiology. URL: https://doi.org/10.1210/endrev/bnac029 (published 13 Nov 2023). (nyberg2023astateof pages 1-1, nyberg2023astateof pages 1-2, nyberg2023astateof pages 2-3)
- Mechanistic consolidation (2023 review): Recent reviews underscore that impaired processing (reduced corin/furin activity or increased proBNP O‑glycosylation), increased PDE activity that lowers cGMP, and increased NPR3 clearance can all contribute to NP resistance, providing multiple intervention points. URL: https://doi.org/10.3390/ijms24065131 (published 7 Mar 2023). (gallo2023natriureticpeptidesit pages 4-5, gallo2023natriureticpeptidesit pages 1-2)
3) Current applications and real-world implementations
- Biomarkers in heart failure and cardiometabolic risk: BNP and NT‑proBNP are standard-of-care biomarkers for diagnosis, risk stratification, and management of heart failure; their use is embedded in clinical practice guidelines. Reviews detail their utility across acute and chronic HF and related conditions, with interpretation modulated by age, renal function, atrial fibrillation (AF), and metabolic status. (gallo2023natriureticpeptidesit pages 1-2, nyberg2023astateof pages 1-2)
- Diagnostic performance in AF and community settings: A large primary-care diagnostic accuracy study (PLOS Medicine, 2025; leveraging 2004–2018 records) found NT‑proBNP discriminated HF more accurately in people without AF (AUC 0.877) than with AF (AUC 0.743). In AF, sensitivity/specificity at 125 pg/mL were 98.8%/13.2%, and at 400 pg/mL were 93.2%/35.5%; in non‑AF, 125 pg/mL yielded 92.9%/53.8%, and 400 pg/mL 77.1%/84.9%. Raising AF thresholds (e.g., to 660 pg/mL) reduced false positives by ~26% but at the cost of more missed cases (−NPV trade‑off). These real-world data inform threshold adjustments and guideline discussions. URL: https://doi.org/10.1371/journal.pmed.1004550 (published 30 Oct 2025). (jones2025ntprobnptestingfor pages 1-2)
- Translational NPR1 agonism: REGN5381 exemplifies ongoing drug development to harness NPR1 signaling for hemodynamic benefit with potentially longer duration than native peptide infusions, which have been limited by short half‑lives. (dunn2024agonistantibodyto pages 1-2)
4) Expert opinions and analysis from authoritative sources
- Systems/physiology perspective: Comprehensive reviews emphasize BNP’s central role in cardio‑renal homeostasis via NPR1‑cGMP‑PKG signaling, leading to natriuresis/vasodilation and anti‑remodeling effects. They also detail the complexity of NP maturation (O‑glycosylation), variable propeptide release under stress, receptor distribution, and clearance pathways (NPR3 and proteolytic degradation), all of which shape biomarker interpretation and therapeutic strategies. URLs: Cells review (2024) https://doi.org/10.3390/cells13110931; IJMS reviews (2023) https://doi.org/10.3390/ijms24119642 and https://doi.org/10.3390/ijms24065131; Endocrine Reviews (2023) https://doi.org/10.1210/endrev/bnac029. (giovou2024theimpactof pages 5-7, corte2023thenatriureticpeptide pages 2-4, gallo2023natriureticpeptidesit pages 4-5, gallo2023natriureticpeptidesit pages 1-2, nyberg2023astateof pages 1-1, nyberg2023astateof pages 1-2, nyberg2023astateof pages 2-3)
- Genetic and pharmacologic insights: The Nature 2024 NPR1 study links human genetics to physiology and therapeutic design, bolstering NPR1 as a validated target; it also situates NP therapeutics (e.g., prior nesiritide/carperitide) within a framework where receptor-selective, long-acting agents may offer clinical advantages. URL: https://doi.org/10.1038/s41586-024-07903-1. (dunn2024agonistantibodyto pages 1-2)
5) Relevant statistics and data from recent studies
- Diagnostic accuracy (primary care; AF vs non‑AF): NT‑proBNP AUC and threshold performance as above: AUC 0.877 (non‑AF) vs 0.743 (AF). Sensitivity/specificity at 125 pg/mL: 92.9%/53.8% (non‑AF) and 98.8%/13.2% (AF). At 400 pg/mL: 77.1%/84.9% (non‑AF) and 93.2%/35.5% (AF). Adjusting AF threshold to 660 pg/mL reduced false positives by 26.0% at the cost of more missed diagnoses; retained NPV ~91.5%. (PLOS Med 2025). URL: https://doi.org/10.1371/journal.pmed.1004550. (jones2025ntprobnptestingfor pages 1-2)
- Genetic effect sizes for NPR1 variants (Nature 2024): Example associations include NPR1 protein-truncating variants with +1.85 mmHg systolic BP (95% CI 0.57–3.14), and a common LOF missense (p.Glu967Lys) with +1.13 mmHg (95% CI 0.92–1.33). A GOF missense (p.Gly541Ser) associated with −0.95 mmHg (95% CI −1.39 to −0.51). Early-phase human data for REGN5381 demonstrated expected venous haemodynamic changes in healthy volunteers. URL: https://doi.org/10.1038/s41586-024-07903-1. (dunn2024agonistantibodyto pages 1-2)
Functional annotation for K9IWC0 (inferred for Desmodus rotundus)
- Molecular function: Secreted peptide hormone that activates NPR1 (GC‑A) to stimulate cGMP production and PKG signaling, mediating natriuresis, diuresis, vasodilation, and anti‑fibrotic/anti‑hypertrophic actions. The disulfide‑bonded ring in the natriuretic peptide domain mediates receptor binding. (gallo2023natriureticpeptidesit pages 4-5, giovou2024theimpactof pages 5-7)
- Biological process: Cardio‑renal homeostasis; counter‑regulation of volume/pressure overload; inhibition of RAAS; suppression of fibrosis/hypertrophy signaling programs in the myocardium. Under stress, ventricular expression is induced. (gallo2023natriureticpeptidesit pages 1-2, nyberg2023astateof pages 1-2)
- Cellular component/localization: Secreted from cardiomyocytes; prohormone processed by corin/furin; cleared by NPR3 and proteolysis. (corte2023thenatriureticpeptide pages 2-4, nyberg2023astateof pages 2-3)
Notes on species-specific evidence
- Bats/Desmodus rotundus: We did not identify recent (2023–2024) primary studies directly characterizing NPPB/BNP in Desmodus rotundus. Given the strong conservation of the natriuretic peptide domain and processing/signaling machinery across mammals, the above functions and pathways are expected to hold for K9IWC0. Future work could assess sequence-specific O‑glycosylation motifs and convertase sites to refine processing predictions. (giovou2024theimpactof pages 5-7)
Limitations and open questions
- Diagnostic thresholds are sensitive to comorbidities (age, AF, renal function, obesity). While guidelines recommend specific cut-offs, threshold optimization (e.g., AF-specific higher cut-offs) trades sensitivity for specificity; implementation should reflect healthcare system priorities and patient mix. Real-world primary care data support such adjustments. (jones2025ntprobnptestingfor pages 1-2)
- Mechanisms of NP deficiency include variable O‑glycosylation and receptor-level bioactivity variation; better biomarkers capturing active vs inactive forms may improve precision diagnostics. (nyberg2023astateof pages 1-1, nyberg2023astateof pages 2-3)
- Translational targeting of processing (corin/furin) and receptor signaling (NPR1 agonists; NPR3 modulation) is promising but requires further clinical validation. (dunn2024agonistantibodyto pages 1-2, gallo2023natriureticpeptidesit pages 4-5)
References (URL and publication date where available)
- Giovou AE, Gladka MM, Christoffels VM. The Impact of Natriuretic Peptides on Heart Development, Homeostasis, and Disease. Cells. 2024 May 31;13:931. URL: https://doi.org/10.3390/cells13110931 (2024-05-31). (giovou2024theimpactof pages 5-7)
- Della Corte V, et al. The Natriuretic Peptide System: A Single Entity, Pleiotropic Effects. Int J Mol Sci. 2023 Jun 7;24:9642. URL: https://doi.org/10.3390/ijms24119642 (2023-06-07). (corte2023thenatriureticpeptide pages 2-4)
- Gallo G, et al. Natriuretic Peptides: It Is Time for Guided Therapeutic Strategies Based on Their Molecular Mechanisms. Int J Mol Sci. 2023 Mar 7;24:5131. URL: https://doi.org/10.3390/ijms24065131 (2023-03-07). (gallo2023natriureticpeptidesit pages 1-2, gallo2023natriureticpeptidesit pages 4-5)
- Nyberg M, et al. A State of Natriuretic Peptide Deficiency. Endocr Rev. 2023 Nov 13;44:379–392. URL: https://doi.org/10.1210/endrev/bnac029 (2023-11-13). (nyberg2023astateof pages 1-1, nyberg2023astateof pages 1-2, nyberg2023astateof pages 2-3)
- Dunn ME, et al. Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone. Nature. 2024 Sep 11;633:654–661. URL: https://doi.org/10.1038/s41586-024-07903-1 (2024-09-11). (dunn2024agonistantibodyto pages 1-2)
- Jones NR, et al. NT-proBNP testing for heart failure diagnosis in people with atrial fibrillation: a diagnostic accuracy study. PLoS Med. 2025 Oct 30;22:e1004550. URL: https://doi.org/10.1371/journal.pmed.1004550 (2025-10-30). (jones2025ntprobnptestingfor pages 1-2)
Acceptance of mandatory verification steps
1) “K9IWC0” is a UniProt accession (not a symbol) mapped here to natriuretic peptide B precursor; description matches natriuretic peptide family. (giovou2024theimpactof pages 5-7)
2) Organism verification: Desmodus rotundus (vampire bat) specified in the prompt; no conflict was found. (giovou2024theimpactof pages 5-7)
3) Protein family/domain alignment: Matches natriuretic peptide family with conserved ring/disulfide and natriuretic peptide domain annotations; signaling via NPR1 is conserved. (corte2023thenatriureticpeptide pages 2-4, giovou2024theimpactof pages 5-7)
4) Ambiguity check: No literature using “K9IWC0” as a gene symbol was used; function is inferred from UniProt entry and conserved BNP/NPPB biology.
Conclusion
K9IWC0 in Desmodus rotundus encodes the BNP precursor whose conserved natriuretic peptide domain, maturation by corin/furin, NPR1‑mediated cGMP signaling, and cardio‑renal endocrine functions are well characterized across mammals. 2023–2024 work refined clinical interpretation (e.g., AF‑specific diagnostic performance), highlighted the concept of NP deficiency and post‑translational maturation (O‑glycosylation), and introduced NPR1 agonist antibody therapy (REGN5381) as a new translational avenue. Species‑specific experimental data in vampire bat remain to be defined, but the strong evolutionary conservation supports these annotations for K9IWC0. (dunn2024agonistantibodyto pages 1-2, jones2025ntprobnptestingfor pages 1-2, nyberg2023astateof pages 1-1, nyberg2023astateof pages 2-3, gallo2023natriureticpeptidesit pages 1-2, giovou2024theimpactof pages 5-7)
References
(giovou2024theimpactof pages 5-7): Alexandra E. Giovou, Monika M. Gladka, and Vincent M. Christoffels. The impact of natriuretic peptides on heart development, homeostasis, and disease. Cells, 13:931, May 2024. URL: https://doi.org/10.3390/cells13110931, doi:10.3390/cells13110931. This article has 20 citations and is from a poor quality or predatory journal.
(corte2023thenatriureticpeptide pages 2-4): Vittoriano Della Corte, Gaetano Pacinella, Federica Todaro, Rosaria Pecoraro, and Antonino Tuttolomondo. The natriuretic peptide system: a single entity, pleiotropic effects. International Journal of Molecular Sciences, 24:9642, Jun 2023. URL: https://doi.org/10.3390/ijms24119642, doi:10.3390/ijms24119642. This article has 31 citations and is from a poor quality or predatory journal.
(giovou2024theimpactof pages 19-20): Alexandra E. Giovou, Monika M. Gladka, and Vincent M. Christoffels. The impact of natriuretic peptides on heart development, homeostasis, and disease. Cells, 13:931, May 2024. URL: https://doi.org/10.3390/cells13110931, doi:10.3390/cells13110931. This article has 20 citations and is from a poor quality or predatory journal.
(nyberg2023astateof pages 2-3): Michael Nyberg, Dijana Terzic, Trine P Ludvigsen, Peter D Mark, Natasha B Michaelsen, Steen Z Abildstrøm, Mads Engelmann, A Mark Richards, and Jens P Goetze. A state of natriuretic peptide deficiency. Endocrine Reviews, 44:379-392, Nov 2023. URL: https://doi.org/10.1210/endrev/bnac029, doi:10.1210/endrev/bnac029. This article has 24 citations and is from a domain leading peer-reviewed journal.
(gallo2023natriureticpeptidesit pages 4-5): Giovanna Gallo, Speranza Rubattu, Camillo Autore, and Massimo Volpe. Natriuretic peptides: it is time for guided therapeutic strategies based on their molecular mechanisms. International Journal of Molecular Sciences, 24:5131, Mar 2023. URL: https://doi.org/10.3390/ijms24065131, doi:10.3390/ijms24065131. This article has 17 citations and is from a poor quality or predatory journal.
(gallo2023natriureticpeptidesit pages 1-2): Giovanna Gallo, Speranza Rubattu, Camillo Autore, and Massimo Volpe. Natriuretic peptides: it is time for guided therapeutic strategies based on their molecular mechanisms. International Journal of Molecular Sciences, 24:5131, Mar 2023. URL: https://doi.org/10.3390/ijms24065131, doi:10.3390/ijms24065131. This article has 17 citations and is from a poor quality or predatory journal.
(nyberg2023astateof pages 1-2): Michael Nyberg, Dijana Terzic, Trine P Ludvigsen, Peter D Mark, Natasha B Michaelsen, Steen Z Abildstrøm, Mads Engelmann, A Mark Richards, and Jens P Goetze. A state of natriuretic peptide deficiency. Endocrine Reviews, 44:379-392, Nov 2023. URL: https://doi.org/10.1210/endrev/bnac029, doi:10.1210/endrev/bnac029. This article has 24 citations and is from a domain leading peer-reviewed journal.
(dunn2024agonistantibodyto pages 1-2): Michael E. Dunn, Aaron Kithcart, Jee Hae Kim, Andre Jo-Hao Ho, Matthew C. Franklin, Annabel Romero Hernandez, Jan de Hoon, Wouter Botermans, Jonathan Meyer, Ximei Jin, Dongqin Zhang, Justin Torello, Daniel Jasewicz, Vishal Kamat, Elena Garnova, Nina Liu, Michael Rosconi, Hao Pan, Satyajit Karnik, Michael E. Burczynski, Wenjun Zheng, Ashique Rafique, Jonas B. Nielsen, Tanima De, Niek Verweij, Anita Pandit, Adam Locke, Naga Chalasani, Olle Melander, Tae-Hwi Schwantes-An, Daniel J. Rader, Marylyn D. Ritchie, JoEllen Weaver, Nawar Naseer, Afiya Poindexter, Khadijah Hu-Sain, Yi-An Ko, Meghan Livingstone, Fred Vadivieso, Stephanie DerOhannessian, Teo Tran, Julia Stephanowski, Monica Zielinski, Ned Haubein, Joseph Dunn, Anurag Verma, Colleen Morse Kripke, Marjorie Risman, Renae Judy, Shefali S. Verma, Yuki Bradford, Scott Dudek, Theodore Drivas, Lance J. Adams, Jackie Blank, Dale Bodian, Derek Boris, Adam Buchanan, David J. Carey, Ryan D. Colonie, F. Daniel Davis, Dustin N. Hartzel, Melissa Kelly, H. Lester Kirchner, Joseph B. Leader, David H. Ledbetter, J. Neil Manus, Christa L. Martin, Raghu P. Metpally, Michelle Meyer, Tooraj Mirshahi, Matthew Oetjens, Thomas Nate Person, Christopher Still, Natasha Strande, Amy Sturm, Jen Wagner, Marc Williams, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Andrew Deubler, Aris Economides, John D. Overton, Jeffrey G. Reid, Katherine Siminovitch, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Maria Sotiropoulos Padilla, Manasi Pradhan, Kia Manoochehri, Thomas D. Schleicher, Louis Widom, Sarah E. Wolf, Ricardo H. Ulloa, Amelia Averitt, Nilanjana Banerjee, Dadong Li, Sameer Malhotra, Deepika Sharma, Jeffrey C. Staples, Xiaodong Bai, Suganthi Balasubramanian, Suying Bao, Boris Boutkov, Siying Chen, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Olga Krasheninina, Rouel Lanche, Adam J. Mansfield, Evan K. Maxwell, George Mitra, Mona Nafde, Sean O’Keeffe, Max Orelus, Razvan Panea, Tommy Polanco, Ayesha Rasool, William Salerno, Kathie Sun, Joshua Backman, Amy Damask, Lee Dobbyn, Manuel Allen Revez Ferreira, Arkopravo Ghosh, Christopher Gillies, Lauren Gurski, Eric Jorgenson, Hyun Min Kang, Michael Kessler, Jack Kosmicki, Alexander Li, Nan Lin, Daren Liu, Jonathan Marchini, Anthony Marcketta, Joelle Mbatchou, Arden Moscati, Charles Paulding, Carlo Sidore, Eli Stahl, Kyoko Watanabe, Bin Ye, Blair Zhang, Andrey Ziyatdinov, Ariane Ayer, Aysegul Guvenek, George Hindy, Jan Freudenberg, Jonas Bovijn, Kavita Praveen, Manav Kapoor, Mary Haas, Moeen Riaz, Olukayode Sosina, Parsa Akbari, Priyanka Nakka, Sahar Gelfman, Sujit Gokhale, Veera Rajagopal, Gannie Tzoneva, Juan Rodriguez-Flores, Esteban Chen, Marcus B. Jones, Michelle G. LeBlanc, Jason Mighty, Lyndon J. Mitnaul, Nirupama Nishtala, Nadia Rana, Jaimee Hernandez, Jennifer Rico Varela, Aris Baras, Luca A. Lotta, Bret J. Musser, Jason Mastaitis, Kishor B. Devalaraja-Narashimha, Andrew J. Rankin, Tammy Huang, Gary Herman, William Olson, Andrew J. Murphy, George D. Yancopoulos, Benjamin A. Olenchock, and Lori Morton. Agonist antibody to guanylate cyclase receptor npr1 regulates vascular tone. Nature, 633:654-661, Sep 2024. URL: https://doi.org/10.1038/s41586-024-07903-1, doi:10.1038/s41586-024-07903-1. This article has 21 citations and is from a highest quality peer-reviewed journal.
(nyberg2023astateof pages 1-1): Michael Nyberg, Dijana Terzic, Trine P Ludvigsen, Peter D Mark, Natasha B Michaelsen, Steen Z Abildstrøm, Mads Engelmann, A Mark Richards, and Jens P Goetze. A state of natriuretic peptide deficiency. Endocrine Reviews, 44:379-392, Nov 2023. URL: https://doi.org/10.1210/endrev/bnac029, doi:10.1210/endrev/bnac029. This article has 24 citations and is from a domain leading peer-reviewed journal.
(jones2025ntprobnptestingfor pages 1-2): Nicholas R. Jones, Kathryn S. Taylor, José M. Ordóñez-Mena, Clare R. Goyder, F. D. Richard Hobbs, and Clare J. Taylor. Nt-probnp testing for heart failure diagnosis in people with atrial fibrillation: a diagnostic accuracy study. PLOS Medicine, 22:e1004550, Oct 2025. URL: https://doi.org/10.1371/journal.pmed.1004550, doi:10.1371/journal.pmed.1004550. This article has 2 citations and is from a highest quality peer-reviewed journal.
This is NPPC (CNP), not NPPB (BNP). The UniProt name is a paralogue
misassignment. Three independent lines say so, and they were all sitting in
plain view:
K9IWC0-bioinformatics/classify_natriuretic_peptide.py; sequences fetched from the UniProt RESTCFGQKLDRIGALSGLGC vs human CNPCFGLKLDRIGSMSGLGC: 3 differences out of 17. Against the BNP ring: 8 of 17.Why it matters for annotation. BNP signals through NPR1/GC-A; CNP signals
through NPR2/GC-B. The UniProt FUNCTION sentence [file:DESRO/K9IWC0/K9IWC0-uniprot.txt
"Acts by specifically binding and stimulating NPR1 to"] is therefore BNP biology
attached to the wrong protein, and any NPR1-specific inference drawn from it
would be wrong. The Vampirome paper gets it right: PMID:23411029.
Recorded as a CURATION knowledge gap to be reported upstream to UniProt.
The deep-research file inherited the error wholesale — it opens with
[file:DESRO/K9IWC0/K9IWC0-deep-research-falcon.md "UniProt K9IWC0 corresponds to
a natriuretic peptide B precursor (BNP prohormone) annotated in Desmodus
rotundus (vampire bat)"] and then spends most of its length on human NT-proBNP
heart-failure diagnostic thresholds, NPR1 agonist antibodies, and AF-adjusted
cut-offs — none of which has anything to do with a salivary vasodilator peptide.
Marked relevance: LOW.
Annotation change. GO:0097746 blood vessel diameter maintenance had been
marked over-annotated. It is direction-neutral (covers constriction and
dilation), and the direction is known: PMID:23411029. Changed to MODIFY → GO:0042311 vasodilation
(verified via OLS as a direct child of GO:0097746). The other four annotations
were sound; GO:0006182 and GO:0007168 are ACCEPTed with the receptor
identity corrected in the summary, since neither GO term names a receptor.
The UniProt record for K9IWC0 (Desmodus rotundus) carries the ARBA-derived
name RecName: Full=Natriuretic peptides B together with the alternative names
"Brain natriuretic factor prohormone" and "Gamma-brain natriuretic peptide". The
same record, however, assigns the protein to PANTHER subfamily
PTHR12167:SF2; C-TYPE NATRIURETIC PEPTIDE, and the source publication for this
transcript describes the abundant salivary natriuretic peptide of D. rotundus
as C-type natriuretic peptide (CNP). The GOA annotations propagated from the
BNP reading (notably GO:0006182 cGMP biosynthetic process justified by
"binding and stimulating NPR1") depend on which paralogue this actually is,
because BNP signals through NPR1/GC-A whereas CNP signals through NPR2/GC-B.
classify_natriuretic_peptide.py fetches the K9IWC0 precursor and the three
human natriuretic peptide precursors (NPPA/P01160, NPPB/P16860, NPPC/P23582)
from the UniProt REST API at run time and computes, for each human paralogue:
PairwiseAligner,The residue count after the ring is diagnostic: ANP and BNP precursors carry a
C-terminal tail beyond the ring, whereas CNP terminates exactly at the second
ring cysteine.
Reproduce with:
uv run python classify_natriuretic_peptide.py
Raw output is saved in results.json.
| Sequence | Length | % identity to K9IWC0 | C-terminal ring | Residues after ring |
|---|---|---|---|---|
| K9IWC0 (query) | 119 | — | CFGQKLDRIGALSGLGC |
0 |
| human NPPA / ANP (P01160) | 151 | 31.9 | CFGGRMDRIGAQSGLGC |
5 |
| human NPPB / BNP (P16860) | 134 | 31.9 | CFGRKMDRISSSSGLGC |
6 |
| human NPPC / CNP (P23582) | 126 | 72.3 | CFGLKLDRIGSMSGLGC |
0 |
Best match: human NPPC / CNP.
K9IWC0 is a C-type natriuretic peptide (CNP/NPPC) orthologue:
CFGQKLDRIGALSGLGC differs from human CNPCFGLKLDRIGSMSGLGC at only 3 of 17 positions, whereas it differs from theMHLSQLLACALLLTLLSL... in both).Consequences for GO annotation:
FUNCTION sentence "Acts by specifically binding and stimulatingGO:0007168 receptor guanylyl cyclase signaling pathway andGO:0006182 cGMP biosynthetic process remain correct, since CNP also actsGO:0005179 hormone activity is retained, as it is for the human NPPCThis is a sequence-based orthology assignment only. No D. rotundus CNP protein
has been purified or assayed, and receptor usage (NPR2 versus NPR1) is inferred
from mammalian CNP biology rather than measured for the bat protein.
id: K9IWC0
gene_symbol: K9IWC0
product_type: PROTEIN
status: DRAFT
taxon:
id: NCBITaxon:9430
label: Desmodus rotundus
description: >-
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.
existing_annotations:
- term:
id: GO:0006182
label: cGMP biosynthetic process
evidence_type: IEA
original_reference_id: GO_REF:0000118
review:
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.
action: ACCEPT
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.
supported_by:
- &id_gc
reference_id: PMID:23411029
supporting_text: >-
These receptors contain at the C-terminus a guanylate cyclase
functional domain that generates the second messenger cGMP for
signaling purposes
reference_section_type: DISCUSSION
- &id_nprb
reference_id: PMID:23411029
supporting_text: >-
CNP interacts with two subtypes of natriuretic peptide receptor,
namely NPR-B and NPR-C.
reference_section_type: DISCUSSION
- reference_id: file:DESRO/K9IWC0/K9IWC0-deep-research-falcon.md
supporting_text: >-
is the cognate receptor for CNP but can contribute to cGMP signaling
in some contexts
- term:
id: GO:0007168
label: receptor guanylyl cyclase signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000118
review:
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.
action: ACCEPT
reason: >-
Directly supported. This is the signalling pathway the peptide
initiates.
supported_by:
- *id_nprb
- *id_gc
- term:
id: GO:0005179
label: hormone activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
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.
action: ACCEPT
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.
supported_by:
- &id_paracrine
reference_id: PMID:23411029
supporting_text: >-
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
reference_section_type: DISCUSSION
- term:
id: GO:0005576
label: extracellular region
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
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 the specific child term is the better
fit.
action: MODIFY
reason: >-
Use GO:0005615 extracellular space, which is the appropriate
granularity for a secreted soluble peptide hormone.
proposed_replacement_terms:
- id: GO:0005615
label: extracellular space
supported_by:
- reference_id: file:DESRO/K9IWC0/K9IWC0-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Secreted'
- reference_id: file:DESRO/K9IWC0/K9IWC0-uniprot.txt
supporting_text: 'SIGNAL 1..23'
- term:
id: GO:0097746
label: blood vessel diameter maintenance
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
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.
action: MODIFY
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_replacement_terms:
- id: GO:0042311
label: vasodilation
supported_by:
- *id_paracrine
- &id_vasodil
reference_id: PMID:23411029
supporting_text: 'The function of bat CNP is related to vasodilation.'
reference_section_type: DISCUSSION
- reference_id: file:DESRO/K9IWC0/K9IWC0-uniprot.txt
supporting_text: >-
Vasoactive {ECO:0000256|ARBA:ARBA00022858,
ECO:0000256|RuleBase:RU003686}.
references:
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
findings:
- statement: >-
The blood vessel diameter maintenance annotation derives from the
Vasoactive keyword, which does not encode the direction of the effect.
supporting_text: >-
Vasoactive {ECO:0000256|ARBA:ARBA00022858,
ECO:0000256|RuleBase:RU003686}.
- id: GO_REF:0000118
title: TreeGrafter-generated GO annotations
findings:
- statement: >-
The cGMP biosynthetic process and receptor guanylyl cyclase signaling
pathway annotations were propagated from the PANTHER natriuretic
peptide tree. Notably, the PANTHER subfamily assigned is
PTHR12167:SF2 "C-TYPE NATRIURETIC PEPTIDE", which contradicts the
ARBA-derived protein name in the same record.
supporting_text: 'PANTHER; PTHR12167:SF2; C-TYPE NATRIURETIC PEPTIDE; 1.'
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings:
- statement: >-
Hormone activity and extracellular region come from combined automated
methods applied to the Hormone and Secreted keywords.
supporting_text: 'Hormone {ECO:0000256|ARBA:ARBA00022702};'
- id: PMID:23411029
title: 'The "Vampirome": Transcriptome and proteome analysis of the principal
and accessory submaxillary glands of the vampire bat Desmodus rotundus, a
vector of human rabies.'
findings:
- statement: >-
The natriuretic peptide abundantly transcribed in the D. rotundus
principal submaxillary gland is C-type natriuretic peptide, and bat
and human CNP share a similar primary sequence and domain structure.
This is the study whose EMBL submission (JAA44981.1, salivary gland)
underlies the K9IWC0 accession.
supporting_text: >-
The bat PS SGs express high transcriptional levels of CNP (Table 4).
reference_section_type: RESULTS
- statement: >-
The authors assign vasodilation as the function of the bat salivary
CNP, placing it alongside PACAP among the vasodilators that support
blood flow during feeding.
supporting_text: 'The function of bat CNP is related to vasodilation.'
reference_section_type: DISCUSSION
- statement: >-
CNP signals through NPR-B (NPR2, guanylate cyclase B) and the
clearance receptor NPR-C (NPR3), not through NPR1. This is the
receptor distinction that the misassigned NPPB name obscures.
supporting_text: >-
CNP interacts with two subtypes of natriuretic peptide receptor,
namely NPR-B and NPR-C.
reference_section_type: DISCUSSION
- statement: >-
Unlike ANP and BNP, CNP acts locally as a paracrine or autoregulator
and is cleared rapidly from the circulation, being present in plasma
at very low concentrations; it is a potent relaxant of arterial and
venous smooth muscle.
supporting_text: >-
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
reference_section_type: DISCUSSION
- statement: >-
The natriuretic peptide receptors carry a C-terminal guanylate cyclase
domain that generates cGMP as the second messenger for vasodilation.
supporting_text: >-
These receptors contain at the C-terminus a guanylate cyclase
functional domain that generates the second messenger cGMP for
signaling purposes
reference_section_type: DISCUSSION
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
PubMed-verified, full text available via PMC. This is the source
publication for the EMBL entry (JAA44981.1) behind K9IWC0 and it names
the bat salivary natriuretic peptide as CNP, in agreement with the
sequence analysis in the local bioinformatics report and against the
ARBA-derived "Natriuretic peptides B" name in UniProt.
- id: file:DESRO/K9IWC0/K9IWC0-bioinformatics/RESULTS.md
title: Sequence classification of K9IWC0 among the natriuretic peptide paralogues
findings:
- statement: >-
Global pairwise alignment against the three human natriuretic peptide
precursors gives 72.3% identity to NPPC/CNP versus 31.9% to each of
NPPB/BNP and NPPA/ANP, identifying K9IWC0 unambiguously as a C-type
natriuretic peptide.
supporting_text: >-
It is 72.3% identical to human NPPC over the full precursor, versus 31.9% to
- statement: >-
The K9IWC0 precursor terminates exactly at the second ring cysteine
with no trailing residues, which matches NPPC and excludes NPPA (5
trailing residues) and NPPB (6).
supporting_text: >-
Its precursor terminates at the ring cysteine (0 trailing residues), matching
- statement: >-
The analysis is sequence-based orthology assignment only; no D.
rotundus natriuretic peptide has been purified or assayed and receptor
usage is inferred from mammalian CNP biology.
supporting_text: >-
This is a sequence-based orthology assignment only.
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Reproducible analysis added with this review. All four sequences are
fetched from the UniProt REST API at run time and the alignment is
computed by Biopython; nothing is hardcoded. Raw output in
results.json, script in classify_natriuretic_peptide.py.
- id: file:DESRO/K9IWC0/K9IWC0-uniprot.txt
title: UniProtKB record for K9IWC0 (K9IWC0_DESRO)
findings:
- statement: >-
The ARBA-derived protein name is "Natriuretic peptides B" with BNP
alternative names, but the PANTHER subfamily in the same record is
PTHR12167:SF2 "C-TYPE NATRIURETIC PEPTIDE". The record is internally
inconsistent about which paralogue this is.
supporting_text: 'RecName: Full=Natriuretic peptides B'
- statement: >-
The FUNCTION block describes cardiac hormone biology acting through
NPR1 to produce cGMP. This text belongs to BNP/ANP; CNP signals
through NPR2. It should not be used to justify NPR1-specific
annotations for this protein.
supporting_text: >-
Acts by specifically binding and stimulating NPR1 to
- statement: >-
The precursor has a signal peptide (1-23) and is annotated as
Secreted, belonging to the natriuretic peptide family.
supporting_text: 'Belongs to the natriuretic peptide family.'
- id: file:DESRO/K9IWC0/K9IWC0-deep-research-falcon.md
title: Deep research report on K9IWC0
findings:
- statement: >-
The report accepted the UniProt "Natriuretic peptides B" name without
checking it and built its entire narrative on BNP cardiac-biomarker
biology (NT-proBNP thresholds, heart failure diagnostics, NPR1 agonist
antibodies), none of which applies to a salivary C-type natriuretic
peptide.
supporting_text: >-
UniProt K9IWC0 corresponds to a natriuretic peptide B precursor (BNP
prohormone) annotated in Desmodus rotundus (vampire bat)
- statement: >-
The report does correctly state the receptor division of labour within
the family, which is what makes the paralogue misassignment
consequential.
supporting_text: 'is the cognate receptor for CNP'
reference_review:
relevance: LOW
correctness: UNVERIFIED
review_notes: >-
LLM-generated survey that propagated the UniProt paralogue
misassignment. It did not consult the PANTHER subfamily assignment in
the same UniProt record, did not find the Vampirome study that names the
bat salivary peptide as CNP, and devoted most of its length to human
heart-failure biomarker literature irrelevant to this protein. Cited
here only as the record of that error and for its correct statement of
family receptor usage.
core_functions:
- description: >-
Secreted C-type natriuretic peptide that acts extracellularly as a
paracrine peptide hormone, binding the receptor guanylyl cyclase NPR2
(GC-B) on vascular smooth muscle to raise cGMP and relax the vessel. In
the vampire bat it is a product of the principal submaxillary salivary
gland and is understood as one of the salivary vasodilators that maintain
blood flow at the bite site.
supported_by:
- reference_id: file:DESRO/K9IWC0/K9IWC0-bioinformatics/RESULTS.md
supporting_text: 'Best match: **human NPPC / CNP**.'
- reference_id: PMID:23411029
supporting_text: >-
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
reference_section_type: DISCUSSION
- reference_id: PMID:23411029
supporting_text: >-
The bat PS SGs express high transcriptional levels of CNP (Table 4).
reference_section_type: RESULTS
molecular_function:
id: GO:0005179
label: hormone activity
directly_involved_in:
- id: GO:0007168
label: receptor guanylyl cyclase signaling pathway
- id: GO:0006182
label: cGMP biosynthetic process
- id: GO:0042311
label: vasodilation
locations:
- id: GO:0005615
label: extracellular space
knowledge_gaps:
- gap_statement: >-
It is undetermined whether the vampire bat salivary CNP acts on the
host at the bite site or on the bat's own tissues, and no vasodilator
activity has been measured for the bat peptide at all.
boundary: >-
What is established is the paralogue identity (72.3% identity to human
NPPC, precursor terminating at the ring cysteine), high transcript
abundance in the principal submaxillary gland, and that mammalian CNP
is a potent smooth muscle relaxant acting through NPR2. What is
missing is any assay of the bat peptide and any demonstration that it
is delivered to the host.
gap_kind:
- BIOLOGY
dark_aspect: BP_DARK
status: OPEN
significance: >-
The whole interpretation of this gene turns on this question: a
host-directed salivary vasodilator is part of the vampire bat feeding
pharmacopoeia, whereas a self-directed paracrine peptide is
unremarkable endothelial biology that happens to be transcribed in a
gland.
resolution: >-
Synthesise the mature bat CNP ring peptide and measure relaxation of
pre-constricted host arterial rings in a myograph, alongside cGMP
accumulation in cells expressing host NPR2; and confirm by targeted
mass spectrometry that the peptide is present in expectorated saliva.
provenance:
- reference_id: PMID:23411029
supporting_text: 'The function of bat CNP is related to vasodilation.'
reference_section_type: DISCUSSION
- gap_statement: >-
The UniProt protein name for this entry assigns the wrong natriuretic
peptide paralogue, and the FUNCTION text describing NPR1 activation is
BNP biology that does not apply to this protein. This is a curation
gap that will keep producing incorrect receptor-specific inferences
until it is corrected upstream.
boundary: >-
The evidence against the name is unambiguous and internal to the
record: PANTHER assigns subfamily PTHR12167:SF2 "C-TYPE NATRIURETIC
PEPTIDE", the source publication names the bat salivary peptide CNP,
and the sequence is 72.3% identical to human NPPC versus 31.9% to
NPPB. No ontology term is missing; the annotation is simply attached
to the wrong paralogue name.
gap_kind:
- CURATION
dark_aspect: MF_DARK
status: OPEN
significance: >-
Downstream consumers inherit the error: the deep research report for
this gene built an entire BNP heart-failure-biomarker narrative on the
incorrect name, and any NPR1-specific GO annotation propagated from
the FUNCTION text would be wrong.
resolution: >-
Report the misassignment to UniProt so the ARBA-derived name and the
BNP FUNCTION block are replaced with C-type natriuretic peptide and
NPR2-based text.
provenance:
- reference_id: file:DESRO/K9IWC0/K9IWC0-uniprot.txt
supporting_text: >-
Acts by specifically binding and stimulating NPR1 to
- reference_id: file:DESRO/K9IWC0/K9IWC0-bioinformatics/RESULTS.md
supporting_text: 'Best match: **human NPPC / CNP**.'
suggested_questions:
- question: >-
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?
experts:
- Ivo M. B. Francischetti
- José M. C. Ribeiro
- question: >-
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?
- question: >-
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?
suggested_experiments:
- hypothesis: >-
Vampire bat salivary CNP is a functional vasodilator acting on host
vasculature through NPR2.
description: >-
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.
experiment_type: Myograph vasorelaxation with receptor-selective cGMP assay
- hypothesis: >-
The peptide is present in expectorated saliva, not merely transcribed in
the gland.
description: >-
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.
experiment_type: Targeted quantitative proteomics
- hypothesis: >-
Salivary CNP expression is a derived feature of sanguivorous bats rather
than the general endothelial expression seen in other mammals.
description: >-
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.
experiment_type: Comparative expression profiling and selection analysis