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62f58d8800004064 Positive regulation of insulin secretion 4 Mouse

Based on my review of the model and the relevant literature, I can now provide a comprehensive assessment of the GO-CAM model for "Positive regulation of insulin secretion 4 (Mouse)" (gomodel:62f58d8800004064).

GO-CAM Model Review: gomodel:62f58d8800004064

Summary

This GO-CAM model represents a signaling pathway involved in the positive regulation of insulin secretion in mouse pancreatic beta cells, focusing on G protein-coupled acetylcholine receptor (Chrm3) activation leading to phospholipase C signaling, which ultimately contributes to insulin secretion.

Strengths of the Model

  1. Pathway Representation:
  2. The model correctly depicts the main components of the acetylcholine signaling pathway in beta cells: M3 muscarinic receptor (Chrm3) → G proteins (Gnaq, Gna11) → phospholipase C-beta (Plcb1) → PKC (Prkcb)
  3. The causal relationships use the appropriate predicate "directly positively regulates" (RO:0002629)

  4. Activities are correctly associated with the "phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway" (GO:0007207)

  5. Molecular Function Annotations:

  6. Appropriate GO terms are used for each activity:

    • Chrm3: "G protein-coupled acetylcholine receptor activity" (GO:0016907)
    • Gnaq/Gna11: "G protein activity" (GO:0003925)
    • Plcb1: "phosphatidylinositol phospholipase C activity" (GO:0004435)
    • Prkcb: "calcium,diacylglycerol-dependent serine/threonine kinase activity" (GO:0004698)

  7. Evidence Support:

  8. The model is well-supported by appropriate evidence codes and literature references
  9. The evidence for Plcb1's role includes direct assay evidence (ECO:0000314) from PMID:9762362

  10. The G protein activities are supported by sequence orthology evidence (ECO:0000266) with human counterparts

  11. Biochemical Detail:

  12. The model correctly shows inputs and outputs for Plcb1, including PIP2 (REACTO_R-ALL-179856) as input and DAG (REACTO_R-ALL-114519) and IP3 (REACTO_R-ALL-114520) as outputs
  13. This biochemical detail accurately reflects the phospholipase C catalytic activity

Areas for Improvement

  1. Incomplete Insulin Secretion Pathway:
  2. Despite the model's title referring to "Positive regulation of insulin secretion," the causal chain ends with PKC activation (Prkcb) without explicitly connecting to insulin secretion
  3. The biological process term "insulin secretion" (GO:0030073) is present in the model objects but not used in the activity annotations

  4. The literature evidence (PMID:27226533) discusses PKC's role in insulin secretion, but this final connection is missing from the model

  5. Cellular Location Details:

  6. All activities are annotated as occurring at the plasma membrane (GO:0005886), which is correct, but the model would benefit from including the cellular context of type B pancreatic cells (CL:0000169), which is listed in the model objects but not used in annotations

  7. Unused Entity in Model:

  8. MGI:MGI:96907 (Marcks Mmus) is listed in the objects but not used in any activity in the model

  9. The literature (PMID:27226533) specifically mentions MARCKS as a PKC substrate involved in this pathway, suggesting that this should be included as a downstream component

  10. Missing Regulatory Mechanisms:

  11. The model doesn't capture the autocrine regulation aspect discussed in PMID:27226533, where exocytosis of insulin granules leads to ATP release, which activates P2Y1 receptors to generate DAG spikes

Suggestions for Improvement

  1. Complete the Pathway to Insulin Secretion:
  2. Add a downstream activity representing insulin secretion (GO:0030073)
  3. Connect PKC (Prkcb) activity to this insulin secretion activity using the appropriate causal relation (RO:0002304 - causally upstream of, positive effect)

  4. Include the cellular location as type B pancreatic cell (CL:0000169)

  5. Add MARCKS as a PKC Substrate:

  6. Include the phosphorylation of MARCKS (MGI:MGI:96907) by PKC as this is a key downstream event

  7. Based on PMID:27226533, MARCKS phosphorylation is directly linked to exocytosis machinery regulation

  8. Expand the Model to Include Autocrine Signaling:

  9. Consider adding additional entities to represent the autocrine feedback loop described in the literature, where insulin exocytosis leads to ATP release and P2Y1 receptor activation

  10. Add Input/Output Molecules for Additional Activities:

  11. Include input/output specifications for G protein and PKC activities to improve model clarity, similar to what was done for Plcb1

Conclusion

The GO-CAM model "Positive regulation of insulin secretion 4 (Mouse)" provides a good representation of the early steps in the G protein-coupled acetylcholine receptor signaling pathway that contributes to insulin secretion in mouse pancreatic beta cells. The model correctly depicts the causality from receptor activation to PKC activation through G proteins and phospholipase C, with appropriate molecular function terms and evidence.

However, the model would benefit from explicit connection to insulin secretion as the ultimate outcome, inclusion of MARCKS as a PKC substrate, and representation of the cellular context in type B pancreatic cells. These additions would make the model more complete and better aligned with its title and the supporting literature.

Despite these suggested improvements, the model represents a valuable contribution to our understanding of the molecular mechanisms underlying the regulation of insulin secretion and follows GO-CAM best practices for most aspects of its construction.