Pacemaking through Ca2+ stores interacting as coupled oscillators via membrane depolarization
Pacemaking through Ca2+ stores interacting as coupled oscillators via membrane depolarization
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DOI：
10.1529/biophysj.106.095687
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发表时间：
2007-06-01
影响因子：
3.4
通讯作者：
van Helden, Dirk F.
中科院分区：
文献类型：
--
作者：
Imtiaz, Mohammad S.;Zhao, Jun;van Helden, Dirk F.
本研究旨在探讨淋巴管运动的起搏机制。我们测试的假设，即活性肌醇1，4，5-三磷酸受体（IP 3R）操作的Ca 2+商店作为耦合振荡器相互作用，产生近同步的Ca 2+释放事件和相关的起搏电位，这驱动动作电位和收缩的淋巴平滑肌。内皮素1（ET-1），一种激动剂，已知增强合成的IP 3，静止的淋巴管平滑肌合胞体的应用程序首先增强自发的Ca 2+瞬变和/或细胞内Ca 2+波。然后发生更大的近同步Ca 2+瞬变，导致与动作电位和由此产生的血管运动相关的全局同步Ca 2+瞬变。相反，用硝苯地平阻断L-型Ca 2+通道阻止ET-1诱导近同步Ca 2+瞬变和由此产生的动作电位，仅留下异步Ca 2+瞬变和局部Ca 2+波。这些数据通过淋巴平滑肌模型很好地模拟，该模型具有：1）从IP 3R操作的Ca 2+储存的振荡Ca 2+释放，其引起去极化; 2）L型Ca 2+通道;和3）细胞之间的间隙连接。通过耦合的基于触发器的悬挂物夹带，悬挂物的刺激引起全局起搏器活动。膜电位变化和L-型Ca 2+通道产生更多储存活性的正反馈是该过程的基础，提供了Ca 2+储存振荡器之间的长程电化学耦合。我们的结论是，淋巴起搏介导的耦合基于激活的Ca 2+商店之间的相互作用。它们通过储存激活剂的细胞间和细胞内扩散弱耦合，通过膜电位强耦合。预测细胞系统中基于Ca 2+储存的起搏：1）振荡Ca 2+释放诱导去极化; 2）膜去极化提供正反馈以诱导进一步的储存Ca 2+释放; 3）细胞相互连接。这些条件在包括胃肠、淋巴、尿道和血管组织在内的大量细胞系统以及心脏起搏细胞中得到满足。
This study presents an investigation of pacemaker mechanisms underlying lymphatic vasomotion. We tested the hypothesis that active inositol 1,4,5-trisphosphate receptor ( IP3R)-operated Ca2+ stores interact as coupled oscillators to produce near-synchronous Ca2+ release events and associated pacemaker potentials, this driving action potentials and constrictions of lymphatic smooth muscle. Application of endothelin 1 ( ET-1), an agonist known to enhance synthesis of IP3, to quiescent lymphatic smooth muscle syncytia first enhanced spontaneous Ca2+ transients and/or intracellular Ca2+ waves. Larger near-synchronous Ca2+ transients then occurred leading to global synchronous Ca2+ transients associated with action potentials and resultant vasomotion. In contrast, blockade of L- type Ca2+ channels with nifedipine prevented ET-1 from inducing near-synchronous Ca2+ transients and resultant action potentials, leaving only asynchronous Ca2+ transients and local Ca2+ waves. These data were well simulated by a model of lymphatic smooth muscle with: 1), oscillatory Ca2+ release from IP3R-operated Ca2+ stores, which causes depolarization; 2), L- type Ca2+ channels; and 3), gap junctions between cells. Stimulation of the stores caused global pacemaker activity through coupled oscillator-based entrainment of the stores. Membrane potential changes and positive feedback by L- type Ca2+ channels to produce more store activity were fundamental to this process providing long-range electrochemical coupling between the Ca2+ store oscillators. We conclude that lymphatic pacemaking is mediated by coupled oscillator-based interactions between active Ca2+ stores. These are weakly coupled by inter-and intracellular diffusion of store activators and strongly coupled by membrane potential. Ca2+ store-based pacemaking is predicted for cellular systems where: 1), oscillatory Ca2+ release induces depolarization; 2), membrane depolarization provides positive feedback to induce further store Ca2+ release; and 3), cells are interconnected. These conditions are met in a surprisingly large number of cellular systems including gastrointestinal, lymphatic, urethral, and vascular tissues, and in heart pacemaker cells.