W2: Multi-disciplinary approaches to quantify and model calcium signaling in nervous systems and beyond

Questions, answers, and discussions spurred by Workshop 2 (W2) at CNS*2020 on “Multi-disciplinary approaches to quantify and model calcium signaling in nervous systems and beyond.”

Please address your question, or post your answer in a self-explanatory manner, adding essential references and links to any useful resource in case.

On behalf of the workshop organizers,

Pengxing Cao
Maurizio De Pitta
Ivo Siekmann

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I have 3 questions for Dr. Savtchenko regarding ASTRO software:

  1. Have you investigated the effect of the simplification of the geometry into coaxial cylinders on Ca2+ signals?

  2. What is the spatial resolution of ASTRO (i.e the size of the compartments that are considered well-mixed)?

  3. Is it possible to test the effect of heterogeneous distribution of Ca2+ channels using ASTRO?

Thank you very much for your talk and for your answers!

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Hi, Audrey,
Hope you are well living in Japan.

  1. We did not study the effect of geometrical simplification of Ca dynamics. We usually used the Monte Carlo simulation to check the transition from real geometry to cylindrical geometry.
  2. The minimum size of Astro segment was 100 nm. To my regret, the smaller size gives a significant error.
  3. Yes, of course, you can design any distribution of ca channels as well as other membrane channels.

I am working hard on Astro 3, but we need extra financial support. Just applied for a grant.
Cheers

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Thank you very much for your answers!
I am enjoying my time and work in Japan very much, thank you. I hope everything for you is ok in London in those crazy times.
I am eager to see Astro 3, good luck for the grant! It would be very nice if we could find a way to combine software like Astro with software like STEPS for small compartments such as branchlets of the gliapil!
Best,
Audrey

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This is my attempt to give a better answer to two very good questions by Alexey Brazhe which he asked me after my talk “Statistical analysis of type 1 and type 2 IP3 receptors”

This is Alexey’s question in full:

Thank you very much for a beautiful talk.

  1. Is there support from molecular structures of IP3Rs for the existence of the M1/M2 modes? CryoEM or something.
  2. A couple of decades ago there was an interest in non-Markovian/fractal models for channel dynamics. Any comments on these in comparison to nested (mode vs open/close) Markov models?
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Dear Alexey,

Regarding your question 1: The basis of my argument of relating modal gating to conformational changes in the channel protein is the following very nice study of a potassium channel, published in

Chakrapani, S., Cordero-Morales, J., Jogini, V. et al. On the structural basis of modal gating behavior in K+ channels. Nat Struct Mol Biol 18, 67–74 (2011). https://doi.org/10.1038/nsmb.1968

  1. The authors study mutations of a channel that shows different modes and demonstrate that manipulating a single site restricts the channel to one mode.
  2. The crystal structures of the mutants are analysed and movement is simulated using molecular dynamics.
  3. The single-channel kinetics of individual modes is modelled using Markov models.

In summary, the study shows that the modes of the KcsA channel are associated with different conformational states.

The most closely related study in IP3 receptors might be this one:

Fan, G., Baker, M.R., Wang, Z. et al. Cryo-EM reveals ligand induced allostery underlying InsP3R channel gating. Cell Res 28, 1158–1170 (2018). https://doi.org/10.1038/s41422-018-0108-5

Individual states of Markov models have often been interpreted as representations of conformational states, in my opinion, in most cases with little direct evidence. In contrast, I find the relationship between modes and conformational states as illustrated by Chakrapani et al. (2011) highly convincing.

Best wishes,
Ivo

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