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Based on my thorough review of the GO-CAM model (gomodel:66e382fb00000408), protein information, relevant literature, and GO-CAM annotation guidelines, I can now provide a comprehensive review.

Review of GO-CAM Model: gomodel:66e382fb00000408

Model Overview

Title: Signaling by PACAP/ADCYAP1 mediated by VIPR1 receptor (Human)
Taxon: Human (NCBITaxon:9606)
Status: Production

Model Structure and Components

This model represents the signaling pathway where the neuropeptide PACAP/ADCYAP1 (Pituitary adenylate cyclase-activating polypeptide) activates VIPR1 receptors (Vasoactive intestinal peptide receptor 1), leading to G protein activation and subsequent adenylate cyclase activity, resulting in cAMP production.

The model contains four key activities:

  1. ADCYAP1 (P18509) - Functions as a neuropeptide hormone (GO:0005184) in the extracellular space
  2. VIPR1 (P32241) - Acts as a PACAP receptor (GO:0001634) in the plasma membrane
  3. GNAS (Q5JWF2) - Performs G protein activity (GO:0003925) in the cytosol
  4. ADCY6 (O43306) - Exhibits adenylate cyclase activity (GO:0004016) producing cAMP

Pathway Logic and Evidence Assessment

The model correctly captures the following signaling cascade: - ADCYAP1 (PACAP) binding to VIPR1 receptor (directly positively regulates) - VIPR1 activation of the G protein GNAS (directly positively regulates) - GNAS activation of adenylate cyclase ADCY6 (directly positively regulates) - ADCY6 producing cAMP (has output CHEBI:17489)

All activities are part of the adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), which is appropriate for this model.

Evidence Quality

The model includes high-quality evidence for each activity: - All assertions use direct assay evidence (ECO:0000314) - Evidence is supported by appropriate literature references (PMID:36385145, PMID:17110384, PMID:17916776, etc.) - All activities have proper contributor information and recent dates (2024-09-17)

Strengths of the Model

  1. Accurate Molecular Representation: The model correctly captures the GPCR signaling cascade from ligand binding through G protein activation to second messenger production.

  2. Appropriate Cellular Localization: Each component is correctly localized to its appropriate cellular compartment (extracellular space for PACAP, plasma membrane for VIPR1, cytosol for GNAS).

  3. Strong Evidence Base: The model is well-supported by recent scientific literature, particularly PMID:36385145, which provides detailed structural information on VPAC receptor family peptide binding and selectivity.

  4. Consistent with Current Knowledge: The model accurately represents the known signaling pathway for PACAP activating VIPR1 receptors, leading to G protein (Gs) activation and adenylate cyclase stimulation.

Improvement Opportunities

  1. Consideration of Multiple AC Isoforms: Based on PMID:23842570, there appears to be specificity in which adenylate cyclase isoforms are activated. The model currently only includes ADCY6, but the literature suggests that multiple AC isoforms may be involved in PACAP-VIPR1 signaling. Consider adding a note about potential involvement of other AC isoforms.

  2. Downstream Signaling: The model currently ends at cAMP production. Consider extending the model to include downstream effects of cAMP production, such as PKA activation, which would provide a more complete representation of the pathway.

  3. Receptor Selectivity: PMID:36385145 discusses the selectivity of PACAP for different receptor types (VPAC1R vs PAC1R). The model could potentially note that PACAP can also activate other receptor types (particularly PAC1R) with different affinities.

  4. G Protein Subunit Specification: The model correctly shows GNAS (Gαs) but could potentially include information about the βγ subunits, which according to PMID:17110384 also play a role in adenylate cyclase regulation.

Compliance with GO-CAM Best Practices

The model follows GO-CAM annotation guidelines for signaling receptor activity: - ADCYAP1 correctly enables neuropeptide hormone activity (GO:0005184) - VIPR1 correctly enables PACAP receptor activity (GO:0001634) - The causal relations use appropriate predicates (RO:0002629 - directly positively regulates) - Cellular locations are appropriate for each component

According to the "Signaling receptor activity annotation guidelines," this model correctly represents a protein ligand-activated signaling receptor pathway.

Conclusion

Overall, this GO-CAM model (gomodel:66e382fb00000408) is a high-quality representation of PACAP signaling through VIPR1 receptors leading to adenylate cyclase activation and cAMP production. The model is well-supported by scientific evidence, follows GO-CAM annotation guidelines, and accurately represents the known biology of this signaling pathway.

The model is ready for continued use in production, with minor suggestions for potential enhancements that could provide a more comprehensive view of the signaling cascade.