A Kinetic Model of Single and Clustered IP₃ Receptors in the Absence of Ca²⁺ Feedback

¹ University of California, Irvine
² Los Alamos National Lab
³ Univ. of Pennsylvania Sch. of Med.
⁴ University of Pennsylvannia

^* To whom correspondence should be addressed. E-mail: shuaij{at}uci.edu.

Submitted on March 12, 2007
Revised on April 13, 2007
Accepted on 25 April 2007

	Abstract

Ca²⁺ liberation through inositol 1,4,5-trisphosphate receptor/channels generates complex patterns of spatio-temporal cellular Ca²⁺ signals owing to the biphasic modulation of channel gating by Ca²⁺ itself. These processes have been extensively studied in Xenopus oocytes, where imaging studies have revealed local Ca²⁺ signals ('puffs') arising from clusters of IP₃R, and patch-clamp studies on isolated oocyte nuclei have yielded extensive data on IP₃R gating kinetics. To bridge these two levels of experimental data we developed an IP₃R model, and applied stochastic simulation and transition matrix theory to predict the behavior of individual and clustered IP₃R channels. The channel model consists of four identical, independent subunits, each of which has an IP₃-binding site, together with one activating and one inactivating Ca²⁺ binding site. The channel opens when at least three subunits undergo a conformational change to an 'active' state after binding IP₃ and Ca²⁺. The model successfully reproduces patch-clamp data; including the dependence of open probability, mean open duration and mean close duration on [IP₃] and [Ca²⁺]. Notably, the bi-exponential distribution of open time duration and the dependence of mean open time on [Ca²⁺] are explained by populations of openings involving either three or four active subunits. As a first step toward applying the single IP₃R model to describe cellular responses we then simulated measurements of puff latency following step increases of [IP₃]. Assuming that stochastic opening of a single IP₃R at basal cytosolic [Ca²⁺] and any given [IP₃] has a high probability of rapidly triggering neighboring channels by calcium-induced calcium release to evoke a puff, optimal correspondence with experimental data of puff latencies following photorelease of IP₃ was obtained assuming that the cluster contains 40 - 70 IP₃Rs totally.

Key Words: Calcium, Channel, IP3, Patch Clamp, Puff, Stochastic Dynamics

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