Stationary Ca2+ nanodomains in the presence of buffers with two binding sites

Abstract

We examine closed-form approximations for the equilibrium Ca2+ concentration near a point Ca2+ source representing a Ca2+ channel, in the presence of a mobile Ca2+ buffer with 2:1 Ca2+ binding stoichiometry. We consider buffers with two Ca2+ binding sites activated in tandem and possessing distinct binding affinities and kinetics. This allows to model the impact on Ca2+ nanodomains of realistic endogenous Ca2+ buffers characterized by cooperative Ca2+ binding, such as calretinin. The approximations we present involve a combination or rational and exponential functions, whose parameters are constrained using the series interpolation method that we recently introduced for the case of 1:1 Ca2+ buffers. We conduct extensive parameter sensitivity analysis and show that the obtained closed-form approximations achieve reasonable qualitative accuracy for a wide range of buffers Ca2+ binding properties and other relevant model parameters. In particular, the accuracy of the newly derived approximants exceeds that of the rapid buffering approximation in large portions of the relevant parameter space. STATEMENT OF SIGNIFICANCEClosed-form approximations describing equilibrium distribution of Ca2+ in the vicinity of an open Ca2+ channel proved useful for the modeling of local Ca2+ signals underlying secretory vesicle exocytosis, muscle contraction and other cell processes. Such approximations provide an efficient method for estimating Ca2+ and buffer concentrations without computationally expensive numerical simulations. However, while most biological buffers have multiple Ca2+ binding sites, much of prior modeling work considered Ca2+ dynamics in the presence of Ca2+ buffers with a single Ca2+ binding site. Here we extend modeling work on equilibrium Ca2+ nanodomains to the case of Ca2+ buffers with two binding sites, allowing to gain deeper insight into the impact of more realistic Ca2+ buffers, including cooperative buffers, on cell Ca2+ dynamics.