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Based on my review of the GO-CAM model, the protein information, and the relevant guidelines, I will now provide a thorough review of the GO-CAM model with ID 66e382fb00000449, titled "Signaling by PACAP/ADCYAP1 mediated by VIPR2 receptor (Human)".

GO-CAM Review: Signaling by PACAP/ADCYAP1 mediated by VIPR2 receptor (Human)

Model Summary

This GO-CAM model (gomodel:66e382fb00000449) represents the signaling cascade initiated by PACAP (Pituitary adenylate cyclase-activating polypeptide, or ADCYAP1) through the VIPR2 receptor (Vasoactive intestinal polypeptide receptor 2), leading to activation of G-protein signaling and adenylate cyclase, ultimately resulting in cAMP production. The model describes a key G protein-coupled receptor (GPCR) signaling pathway in human cells.

Biological Accuracy

The model accurately represents the established PACAP/VIPR2 signaling pathway:

  1. ADCYAP1 (PACAP) acts as a neuropeptide hormone in the extracellular space
  2. VIPR2 is correctly represented as a PACAP receptor located in the plasma membrane
  3. GNAS (G protein) activation follows receptor activation
  4. ADCY6 (adenylate cyclase 6) is appropriately shown as producing cAMP

The molecular components and their relationships align with current knowledge from literature. The evidence is well-cited with appropriate PMID references, particularly the detailed structural basis from the cryo-EM study (PMID:35477937) showing how PACAP27 binds to VIPR2 and activates G protein signaling.

GO-CAM Annotation Practices

Molecular Functions

The molecular functions are correctly annotated and appropriate for each protein:

  1. ADCYAP1 (P18509): Annotated with "neuropeptide hormone activity" (GO:0005184) - correct for a secreted signaling peptide
  2. VIPR2 (P41587): Annotated with "pituitary adenylate cyclase-activating polypeptide receptor activity" (GO:0001634) - specific and appropriate
  3. GNAS (Q5JWF2): Annotated with "G protein activity" (GO:0003925) - correct for this G-alpha subunit
  4. ADCY6 (O43306): Annotated with "adenylate cyclase activity" (GO:0004016) - appropriate for its enzymatic function

Cellular Location

Cellular locations are correctly specified:

  1. ADCYAP1: Extracellular space (GO:0005615) - correct for a secreted neuropeptide
  2. VIPR2: Plasma membrane (GO:0005886) - appropriate for a membrane-bound receptor
  3. GNAS: Cytosol (GO:0005829) - proper location for G protein signaling
  4. ADCY6: Not explicitly annotated with cellular location, which is a minor omission as it should be plasma membrane-associated

Biological Process

All activities are appropriately annotated as part of the "adenylate cyclase-activating G protein-coupled receptor signaling pathway" (GO:0007189), which is the correct classification for this pathway.

Causal Relationships

The causal flow through the pathway is well-represented:

  1. ADCYAP1 → VIPR2: "directly positively regulates" (RO:0002629) - correct for ligand activation of receptor
  2. VIPR2 → GNAS: "directly positively regulates" (RO:0002629) - appropriate for receptor activation of G protein
  3. GNAS → ADCY6: "directly positively regulates" (RO:0002629) - correct for G protein stimulation of adenylate cyclase
  4. ADCY6 has CHEBI:17489 (3',5'-cyclic AMP) as output - correctly representing the product of the enzymatic reaction

These relationships follow the GO-CAM guidelines for representing GPCR signaling pathways.

Evidence Quality

Each annotation is supported by appropriate evidence:

  1. Direct assay evidence (ECO:0000314) and mutant phenotype evidence (ECO:0000315) from published literature
  2. Use of multiple PMIDs provides strong support for the model
  3. Key references include structural studies (PMID:35477937) showing the PACAP-VIPR2-G protein complex

Recommendations for Improvement

While this is a well-constructed GO-CAM model, I have a few minor suggestions for improvement:

  1. Add cellular location for ADCY6: Explicitly annotate ADCY6 with "plasma membrane" (GO:0005886) as its cellular location, as adenylate cyclase 6 is a membrane-bound enzyme.

  2. Consider expanding pathway context: The model could be expanded to include downstream effects of cAMP production, such as activation of protein kinase A (PKA) or effects on ion channels, which would provide more biological context.

  3. Include small molecule regulators: The model could be enhanced by including known pharmacological regulators of this pathway, such as forskolin (an adenylate cyclase activator).

  4. Add tissue specificity information: Contextual information about where this signaling is most relevant (e.g., neural tissue, immune cells) would enhance the biological relevance of the model.

Conclusion

The GO-CAM model "Signaling by PACAP/ADCYAP1 mediated by VIPR2 receptor (Human)" is accurate, well-evidenced, and follows GO-CAM annotation best practices. It correctly represents the signaling cascade from PACAP activation of VIPR2 through G protein-mediated activation of adenylate cyclase and production of cAMP. The model provides a clear view of this important signaling pathway and could serve as a useful reference for researchers studying GPCR signaling, particularly in the context of PACAP/VIP signaling systems.