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Based on the review of the above model, literature, and GO-CAM guidelines, I will now provide a detailed review of GO-CAM model "gomodel:66e382fb00000583" (Signaling by PACAP/ADCYAP1 mediated by PAC1R/ADCYAP1R1 receptor in Human).

Review of GO-CAM Model: gomodel:66e382fb00000583

Model Summary

The model represents "Signaling by PACAP/ADCYAP1 mediated by PAC1R/ADCYAP1R1 receptor (Human)" and describes the signaling pathway where pituitary adenylate cyclase-activating polypeptide (PACAP/ADCYAP1) activates its receptor PAC1R/ADCYAP1R1, leading to G protein (GNAS) activation and subsequent stimulation of adenylate cyclase (ADCY6), resulting in cAMP production.

Strengths of the Model

  1. Appropriate Molecular Functions:
  2. ADCYAP1 (P18509) is correctly annotated with neuropeptide hormone activity (GO:0005184)
  3. PAC1R/ADCYAP1R1 (P41586) uses appropriate pituitary adenylate cyclase-activating polypeptide receptor activity (GO:0001634)
  4. GNAS (Q5JWF2) uses G protein activity (GO:0003925)

  5. ADCY6 (O43306) uses adenylate cyclase activity (GO:0004016)

  6. Biological Process Context:

  7. All activities are correctly part of the adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189)

  8. Cellular Component Context:

  9. Appropriate cellular locations used: ADCYAP1 in extracellular space (GO:0005615), PAC1R in plasma membrane (GO:0005886), GNAS in cytosol (GO:0005829)

  10. Causal Relationships:

  11. The model correctly represents the signaling cascade:

    • ADCYAP1 directly positively regulates PAC1R (RO:0002629)
    • PAC1R directly positively regulates GNAS (RO:0002629)
    • GNAS directly positively regulates ADCY6 (RO:0002629)

  12. Evidence:

  13. Each activity is well supported by primary research articles with appropriate evidence codes (ECO:0000314 - direct assay evidence used in manual assertion)

Suggested Improvements

  1. Product of Adenylate Cyclase Activity:

  2. The model correctly shows ADCY6 producing cAMP (CHEBI:17489) as output, but this could be enhanced by adding a subsequent step showing cAMP's role in activating protein kinase A, which would make the functional outcome of the pathway clearer.

  3. Potential Missing Component:

  4. The model doesn't explicitly represent the Gβγ subunits of the heterotrimeric G protein complex. While the paper by Gao et al. (2017) mentioned in evidence suggests interactions between ADCY6 and GNB1/GNG2, these aren't included in the model. Consider adding these if there's sufficient evidence for their specific role in this signaling pathway.

  5. Additional Regulatory Elements:

  6. Based on the UniProt entries, calcium ions inhibit ADCY6 at micromolar concentrations. If supported by evidence, this regulatory mechanism could be added to provide a more complete picture of the signaling pathway regulation.

Consistency with GO-CAM Guidelines

  1. Receptor Signaling Guidelines:

  2. The model follows the guidelines for protein ligand-activated signaling receptor activity:

    • ADCYAP1 is correctly annotated with neuropeptide hormone activity (a descendant of receptor ligand activity)
    • It occurs in the extracellular space
    • It directly positively regulates the receptor activity of PAC1R
    • PAC1R is correctly annotated with PACAP receptor activity
    • PAC1R occurs in the plasma membrane
    • The causal relations between components follow the appropriate pattern

  3. G Protein Signaling:

  4. The G protein (GNAS) activity is appropriately represented as mediating between the receptor and adenylate cyclase
  5. The model correctly shows GNAS positively regulating ADCY6 (adenylate cyclase)

Biological Accuracy

  1. Consistency with Literature:
  2. The model accurately represents the well-established PACAP signaling pathway as described in the literature
  3. The cryo-EM structure of PAC1R (PMID:36385145) confirms the interaction between PACAP and PAC1R

  4. The functional studies (PMID:17916776) support the role of ADCY6 in the pathway

  5. Species Specificity:

  6. The model appropriately specifies human proteins and the human context (NCBITaxon:9606)

Conclusion

This GO-CAM model (gomodel:66e382fb00000583) is well-constructed and accurately represents the PACAP/ADCYAP1 signaling pathway through PAC1R/ADCYAP1R1, GNAS, and ADCY6. It follows GO-CAM best practices for representing receptor signaling pathways and is supported by appropriate evidence.

The model could potentially be enhanced by including downstream effects of cAMP production and possibly including additional regulatory mechanisms, but as it stands, it provides a clear and accurate representation of this signaling pathway.