Termination of Ca2+ Release for Clustered IP3R Channels

In many cell types, release of calcium ions is controlled by inositol 1,4,5-trisphosphate () receptor channels. Elevations in concentration after intracellular release through receptors (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 signals and their dependence on residual microdomains. Our general idea is that microdomains are dynamical and mediate the effect of other physiological processes. Specifically, we focus on the mechanism by which binding proteins (buffers) alter the lifetime of signals. We use stochastic simulations of channel gating coupled to a coarse-grained description for the concentration. To describe the 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 inhibition while unbinding is responsible for termination of waves. Thus our analysis hints at an additional role of and shows how cells can make use of the full complexity in R gating behavior to achieve different signals. Author Summary: Calcium signals are important for a host of cellular processes such as neurotransmitter release, cell contraction and gene expression. While the principles of activation and spreading of calcium signals have been largely understood, it is much less clear how their spatio-temporal appearance is shaped. This issue is of high relevance since the spatio-temporal signature is thought to carry the information content. In our paper we study the dynamical mechanisms that determine the time course of calcium release from receptor channels. We use a stochastic channel description combined with a recently developed model for the distribution of released calcium in a microdomain. The simulations uncover a complex control mechanism, which allows for the tuning of release from short frequent puffs to extended and less frequent wave-like release. Unexpectedly, the model predicts that for wave-like release the dissociation of from the receptors leads to termination of the calcium signal. This effect relies on a well-known gating property of R channels, which earlier has been regarded as superfluous in studies for groups of channels. Our results also provide a missing link to understand cellular response to calcium-binding proteins and present a novel mechanism for information processing by R channels.