Modeling Ca2+ feedback on a single inositol 1,4,5-trisphosphate receptor and its modulation by Ca2+ buffers
Modeling Ca2+ feedback on a single inositol 1,4,5-trisphosphate receptor and its modulation by Ca2+ buffers
复制标题
DOI：
10.1529/biophysj.108.137182
复制
发表时间：
2008-10-15
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
肌醇1，4，5-三磷酸受体/通道（IP 3R）是细胞内Ca 2+信号传导的主要调节剂，并且响应于IP 3和Ca 2+两者在胞质位点的结合而从内质网释放Ca 2+离子。虽然IP 3R的稳态门控特性已被广泛研究，并在固定的[IP 3]和[Ca 2 +]的条件下建模，但很少有人知道通过通道的Ca 2+流量如何通过反馈到激活和抑制Ca 2+结合位点来调节同一通道的门控。因此，我们模拟了单体和四聚体IP 3R模型上的Ca 2+自反馈动力学。一个主要的结论是，自激活关键取决于固定的胞质Ca 2+缓冲液，减缓关闭后的本地[Ca 2 +]微区的崩溃。这促进了爆发样的重新开放的重新结合的Ca 2+的激活网站，而抑制作用基本上是独立的固定缓冲液，但强烈依赖于IP 3R上的抑制性Ca 2+结合位点的位置相对于通道孔。
The inositol 1,4,5-trisphosphate receptor/channel (IP3R) is a major regulator of intracellular Ca2+ signaling, and liberates Ca2+ ions from the endoplasmic reticulum in response to binding at cytosolic sites for both IP3 and Ca2+. Although the steady-state gating properties of the IP3R have been extensively studied and modeled under conditions of fixed [IP3] and [Ca2+], little is known about how Ca2+ flux through a channel may modulate the gating of that same channel by feedback onto activating and inhibitory Ca2+ binding sites. We thus simulated the dynamics of Ca2+ self-feedback on monomeric and tetrameric IP3R models. A major conclusion is that self-activation depends crucially on stationary cytosolic Ca2+ buffers that slow the collapse of the local [Ca2+] microdomain after closure. This promotes burst-like reopenings by the rebinding of Ca2+ to the activating site; whereas inhibitory actions are substantially independent of stationary buffers but are strongly dependent on the location of the inhibitory Ca2+ binding site on the IP3R in relation to the channel pore.