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

We examine closed-form approximations for the equilibrium Ca²⁺ and buffer concentrations near a point Ca²⁺ source representing a Ca²⁺ channel, in the presence of a mobile buffer with two Ca²⁺ binding sites activated sequentially and possessing distinct binding affinities and kinetics. This allows us 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 simpler Ca²⁺ buffers with a single Ca²⁺ binding site. We conduct extensive parameter sensitivity analysis and show that the obtained closed-form approximations achieve reasonable qualitative accuracy for a wide range of buffer's Ca²⁺ binding properties and other relevant model parameters. In particular, the accuracy of the derived approximants exceeds that of the rapid buffering approximation in large portions of the relevant parameter space.