Mapping Interpuff Interval Distribution to the Properties of Inositol Trisphosphate Receptors

Tightly clustered inositol trisphosphate receptors (IP₃Rs) control localized Ca²⁺ liberation from the endoplasmic reticulum to generate repetitive Ca²⁺ puffs. Distributions of the interpuff interval (IPI), i.e., the waiting time between successive puffs, are found to be well characterized by a probability density function involving only two parameters, λ and ξ, which represent the basal rate of puff generation and the recovery rate from refractoriness, respectively. However, how the two parameters depend on the kinetic parameters of single IP₃Rs in a cluster is still unclear. In this article, using a stochastic puff model and a single-channel data-based IP₃R model, we establish the dependencies of λ and ξ on two important IP₃R model parameters, IP₃ concentration ([IP₃]) and the recovery rate from Ca²⁺ inhibition (r_low). By varying [IP₃] and r_low in physiologically plausible ranges, we find that the ξ-λ plane is comprised of only two disjoint regions, a biologically impermissible region and a region where each parameter set (ξ, λ) can be caused by using two different combinations of [IP₃] and r_low. The two combinations utilize very different mechanisms to maintain the same IPI distribution, and the mechanistic difference provides a way of identifying IP₃R kinetic parameters by observing properties of the IPI.