ukemi
commented
1 year ago - [x] Make mouse models: http://noctua.geneontology.org/editor/graph/gomodel:62f58d8800004529? and http://noctua.geneontology.org/editor/graph/gomodel:62f58d8800004803?
- [x] Fill in molecular events
- [x] Check the evidence that PKA acts on ion channels and membrane potential. PMID:23349500 makes a GOF for Prkaca and shows the action is downstream of at least the calcium membrane flux. PMID:26216970 identifies synaptotagmin 7 as a target of PKA that potentiates insulin secretion. However, things may be more complicated: PMID:8381211.
- [x] PMIID:17510178 supports that the two pathways, EPAC and PKA, result in increased exocytosis of SVs and LVs respectively. LVs contain insulin. We need to investigate the evidence supporting the EPAC pathway in insulin secretion. Is insulin not found in the small vesicles (PMID:7907072)?
- [x] R-HSA-381644 acts in the ER membrane, but diagram shows it in the plasma membrane. FIXED
- [ ] There are two reactions in Reactome representing the adenylate cyclase step of the pathway, R-HSA-381607 and R-HSA-164377. The former is catalyzed by ADCY8 and the latter is catalyzed by a set of all ADCYs. I have curated the ADCY8 for the mouse, but not the rest of the family members. My model shows the evidence for the involvement of ADCY8. Basically, it is a mutational study that shows the gene product is necessary for GLP1 signaling. However, digging a bit more into ADCY8, I see that it is a calcium-activated adenylate cyclase. An alternative hypothesis to it being directly activated by Gas is that it is activated by the downstream Ca+2 flux and is actually involved in maintaining the high cAMP levels needed to sustain insulin secretion... or both. There is no way to mention this kind of caveat in the model. Why does Reactome have the two reactions? Good question - ask Bruce May (curator) whether these reactions can be merged or, alternatively, better distinguished.