From Local to Global Modeling for Characterizing Calcium Dynamics and Their Effects on Electrical Activity and Exocytosis in Excitable Cells.

Francesco Montefusco,Morten Pedersen

doi:10.3390/ijms20236057

Francesco Montefusco, Morten Pedersen

Open Access

https://doi.org/10.3390/ijms20236057

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Abstract

Electrical activity in neurons and other excitable cells is a result of complex interactions between the system of ion channels, involving both global coupling (e.g., via voltage or bulk cytosolic Ca2+ concentration) of the channels, and local coupling in ion channel complexes (e.g., via local Ca2+ concentration surrounding Ca2+ channels (CaVs), the so-called Ca2+ nanodomains). We recently devised a model of large-conductance BKCa potassium currents, and hence BKCa–CaV complexes controlled locally by CaVs via Ca2+ nanodomains. We showed how different CaV types and BKCa–CaV stoichiometries affect whole-cell electrical behavior. Ca2+ nanodomains are also important for triggering exocytosis of hormone-containing granules, and in this regard, we implemented a strategy to characterize the local interactions between granules and CaVs. In this study, we coupled electrical and exocytosis models respecting the local effects via Ca2+ nanodomains. By simulating scenarios with BKCa–CaV complexes with different stoichiometries in pituitary cells, we achieved two main electrophysiological responses (continuous spiking or bursting) and investigated their effects on the downstream exocytosis process. By varying the number and distance of CaVs coupled with the granules, we found that bursting promotes exocytosis with faster rates than spiking. However, by normalizing to Ca2+ influx, we found that bursting is only slightly more efficient than spiking when CaVs are far away from granules, whereas no difference in efficiency between bursting and spiking is observed with close granule-CaV coupling.

Highlights

Mathematical modeling has played an important role in characterizing the electrical properties of neurons and other excitable cells
We show the role of mathematical modeling as an important tool for investigating excitable cells with focus on ion Ca2+channels and their local interactions with BKCa potassium channels in influencing electrical activity of pituitary cells and with hormone-containing granules determining the granule release by exocytosis process
In order to handle the local interactions in BKCa–CaV complexes with 1:n stoichiometry, we used a stochastic model based on Markov chain theory, as a starting point for analyzing the single complex dynamics

Summary

Introduction

Mathematical modeling has played an important role in characterizing the electrical properties of neurons and other excitable cells. By applying MC theory [11], reaction-diffusion models [10] and time scale analysis [12] to a more realistic BKCa–CaV complex with 1:n stoichiometry, we [13] obtained a mechanistically correct model of the BKCa current, which respects the local effects of BKCa–CaV coupling, and can be inserted in Hodgkin–Huxley-type models of whole-cell electrical activity: different CaV types and BKCa–CaV stoichiometries affect BKCa channel activity and the resulting whole-cell electrical activity in neurons and other excitable cells This kind of local-global modeling is similar to previous work on Ca2+ dynamics in cardiac cells [14]

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