Termination of Ca(2+) Release for Clustered IP(3)R Channels

In many cell types, release of calcium ions is controlled by inositol 1,4,5-trisphosphate ([Image: see text]) receptor channels. Elevations in [Image: see text] concentration after intracellular release through [Image: see text] receptors ([Image: see text]R) can either propagate in the form of waves spreading through the entire cell or produce spatially localized puffs. The appearance of waves and puffs is thought to implicate random initial openings of one or a few channels and subsequent activation of neighboring channels because of an “autocatalytic” feedback. It is much less clear, however, what determines the further time course of release, particularly since the lifetime is very different for waves (several seconds) and puffs (around 100 ms). Here we study the lifetime of [Image: see text] signals and their dependence on residual [Image: see text] microdomains. Our general idea is that [Image: see text] microdomains are dynamical and mediate the effect of other physiological processes. Specifically, we focus on the mechanism by which [Image: see text] binding proteins (buffers) alter the lifetime of [Image: see text] signals. We use stochastic simulations of channel gating coupled to a coarse-grained description for the [Image: see text] concentration. To describe the [Image: see text] concentration in a phenomenological way, we here introduce a differential equation, which reflects the buffer characteristics by a few effective parameters. This non-stationary model for microdomains gives deep insight into the dynamical differences between puffs and waves. It provides a novel explanation for the different lifetimes of puffs and waves and suggests that puffs are terminated by [Image: see text] inhibition while [Image: see text] unbinding is responsible for termination of waves. Thus our analysis hints at an additional role of [Image: see text] and shows how cells can make use of the full complexity in [Image: see text]R gating behavior to achieve different signals.