Modeling Ca2+ currents and buffered diffusion of Ca2+ in human β-cells during voltage clamp experiments

• Mathematical models of the L, T and P/Q macroscopic Ca2+ currents were developed.
• A novel framework for including spatial aspects to models of the β-cell is proposed.
• Ca2+ nanodomains are produced under high buffering conditions during simulations of voltage clamp experiments in human β-cells.
• Ca2+ nanodomains do not overlap in simulations of voltage clamp experiments.
• The contribution of each current to the formation of the Ca2+ nanodomains was estimated.

Macroscopic Ca2+ currents of the human β-cells were characterized using the Hodgkin–Huxley formalism. Expressions describing the Ca2+-dependent inactivation process of the L-type Ca2+ channels in terms of the concentration of Ca2+ were obtained. By coupling the modeled Ca2+ currents to a three-dimensional model of buffered diffusion of Ca2+, we simulated the Ca2+ transients formed in the immediate vicinity of the cell membrane during voltage clamp experiments performed in high buffering conditions. Our modeling approach allowed us to consider the distribution of the Ca2+ sources over the cell membrane. The effect of exogenous (EGTA) and endogenous Ca2+ buffers on the temporal course of the Ca2+ transients was evaluated. We show that despite the high Ca2+ buffering capacity, nanodomains are formed in the submembrane space, where a peak Ca2+ concentration between ∼76 and 143 µM was estimated from our simulations. In addition, the contribution of each Ca2+ current to the formation of the Ca2+ nanodomains was also addressed. Here we provide a general framework to incorporate the spatial aspects to the models of the pancreatic β-cell, such as a more detailed and realistic description of Ca2+ dynamics in response to electrical activity in physiological conditions can be provided by future models.

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