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T-World 4: Problem 2 - Coupling ICaL and RyR

 To address the issue of timing of calcium rise in the junctional dyad, I first tried to just facilitate the calcium-sensitivity of release. Nope, again too fidgety and prone to spontaneous release when pushing the sensitivity too far.

I then had an idea I was slightly proud of – that was after I had the bucket size insight. I thought – ok, let’s split the dyad into an “inner dyad”, which is even smaller, and where ICaL and RyR meet, and an “outer dyad”, where e.g. the Na-Ca exchanger could reside. In this way, we would have even tighter coupling with a smaller bucket, and thus faster dynamics. Going over papers on dyad sizes and counts, a back-of-an-envelope calculation revealed we can push the inner dyad size down quite a bit. This has worked really well for a lot of aspects, we had nice calcium dynamics, alternans, DADs, all looked pink and rosy. Except then I realised that the model had massive issue with the release being far too refractory. I tried to address it, but could not (even with genetic algorithms etc.). I was quite stuck.

Then I came up with an alternative – somewhat less elegant in my view – the tightest coupling could be represented by a small population of RyR directly coupled to ICaL (like in ToR-ORd), which would provide enough early calcium rise to trigger the much larger population of more standard Bers/Grandi RyRs. This should also facilitate fast rise of calcium and should be less prone to issues with refractoriness… and it was!

So, then I went forward with this alternative, and it actually made it throughout the years to the final version. It was really hard to let go the two-tier dyad idea, which seemed elegant and I was working with it for over a year. I was switching to a markedly different system which initially didn’t work as well in some regards – but it could be ultimately developed much further.

This choice also illustrates a common situation in model development – you just go for the more promising option, not knowing if it will be the ultimately used one. Sometimes it happened that this more promising option would lead me to an even more desperately stuck state, so then I’d revisit a prior idea that I left in a drawer as unpromising… or yet another idea. I’d draw trees of what options are left to achieve what I wanted. Often one gets more experience in one development branch that can be used to fix issues in other branches. Of course, sometimes just nothing works.

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