A kinetic model of single and clustered IP3 receptors in the absence of Ca2+ feedback
A kinetic model of single and clustered IP3 receptors in the absence of Ca2+ feedback
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DOI：
10.1529/biophysj.107.108795
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发表时间：
2007-08-01
影响因子：
3.4
通讯作者：
Parker, Ian
中科院分区：
文献类型：
--
作者：
Shuai, Jianwei;Pearson, John E.;Parker, Ian
由于 Ca2+ 本身对通道门控的双相调节，通过肌醇 1,4,5-三磷酸受体 (IP3R) 通道释放 Ca2+ 会产生复杂的时空细胞 Ca(2+) 信号模式。这些过程已在非洲爪蟾卵母细胞中进行了广泛研究，其中成像研究揭示了由 IP3R 簇产生的局部 Ca2+ 信号（“泡芙”），对分离卵母细胞核的膜片钳研究已产生有关 IP3R 门控动力学的大量数据。为了桥接这两个水平的实验数据，我们开发了一个 IP3R 模型并应用随机模拟和转移矩阵理论来预测单个和集群 IP(3)R 通道的行为。通道模型由四个组成相同、独立的亚基，每个亚基都有一个 IP3- 结合位点以及一个激活和一个失活的 Ca2+- 结合位点，当至少三个亚基在 IP3 和 Ca2+ 结合后发生构象变化至“活性”状态时，该通道就会打开。该模型成功地再现了膜片钳数据；包括开放概率、平均开放持续时间和平均关闭持续时间对 [IP3] 和 [Ca2+] 的依赖性。值得注意的是，开放时间持续时间的双指数分布和平均开放时间对[Ca2+]的依赖性可以通过涉及三个或四个活性亚基的开放群体来解释。作为一个。应用单一 IP3R 模型来描述细胞反应的第一步，然后我们模拟了 [IP3] 逐步增加后的抽吸潜伏期的测量。假设在基础胞质 [Ca2+] 和任何给定的 [IP3] 处随机打开单个 IP3R 很有可能通过钙诱导的钙释放快速触发邻近通道以引起抽吸，则当簇包含总共 40 - 70 个 IP(3)R 时，获得与 IP3 光释放后抽吸潜伏期实验数据的最佳对应关系。
Ca2+ liberation through inositol 1,4,5- trisphosphate receptor (IP3R) channels generates complex patterns of spatiotemporal cellularCa(2+) 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 IP(3)Rchannels. 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 closed duration on [IP3] and [Ca2+]. Notably, the biexponential 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. rst step toward applying the single IP3R model to describe cellular responses, we then simulated measurements of puff latency after 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 after photorelease of IP3 was obtained when the cluster contained a total of 40 - 70 IP(3)Rs.