Imtiaz Mohammad S, Zhao Jun, Hosaka Kayoko, von der Weid Pierre-Yves, Crowe Melissa, van Helden Dirk F
Neuroscience Group, School of Biomedical Sciences, Faculty of Health, The University of Newcastle, Newcastle, Australia.
Biophys J. 2007 Jun 1;92(11):3843-61. doi: 10.1529/biophysj.106.095687. Epub 2007 Mar 9.
This study presents an investigation of pacemaker mechanisms underlying lymphatic vasomotion. We tested the hypothesis that active inositol 1,4,5-trisphosphate receptor (IP(3)R)-operated Ca(2+) stores interact as coupled oscillators to produce near-synchronous Ca(2+) 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 IP(3), to quiescent lymphatic smooth muscle syncytia first enhanced spontaneous Ca(2+) transients and/or intracellular Ca(2+) waves. Larger near-synchronous Ca(2+) transients then occurred leading to global synchronous Ca(2+) transients associated with action potentials and resultant vasomotion. In contrast, blockade of L-type Ca(2+) channels with nifedipine prevented ET-1 from inducing near-synchronous Ca(2+) transients and resultant action potentials, leaving only asynchronous Ca(2+) transients and local Ca(2+) waves. These data were well simulated by a model of lymphatic smooth muscle with: 1), oscillatory Ca(2+) release from IP(3)R-operated Ca(2+) stores, which causes depolarization; 2), L-type Ca(2+) 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 Ca(2+) channels to produce more store activity were fundamental to this process providing long-range electrochemical coupling between the Ca(2+) store oscillators. We conclude that lymphatic pacemaking is mediated by coupled oscillator-based interactions between active Ca(2+) stores. These are weakly coupled by inter- and intracellular diffusion of store activators and strongly coupled by membrane potential. Ca(2+) store-based pacemaking is predicted for cellular systems where: 1), oscillatory Ca(2+) release induces depolarization; 2), membrane depolarization provides positive feedback to induce further store Ca(2+) 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.
本研究对淋巴管运动的起搏器机制进行了调查。我们检验了以下假设：活性肌醇1,4,5-三磷酸受体（IP₃R）操纵的钙库作为耦合振荡器相互作用，以产生近同步的钙释放事件和相关的起搏器电位，进而驱动动作电位和淋巴管平滑肌的收缩。将内皮素1（ET-1）（一种已知可增强IP₃合成的激动剂）应用于静止的淋巴管平滑肌细胞团，首先增强了自发钙瞬变和/或细胞内钙波。随后出现更大的近同步钙瞬变，导致与动作电位和由此产生的血管运动相关的全局同步钙瞬变。相比之下，用硝苯地平阻断L型钙通道可阻止ET-1诱导近同步钙瞬变和由此产生的动作电位，仅留下异步钙瞬变和局部钙波。这些数据通过一个淋巴管平滑肌模型得到了很好的模拟，该模型具有：1）从IP₃R操纵的钙库中进行振荡性钙释放，这会导致去极化；2）L型钙通道；3）细胞间的缝隙连接。对钙库的刺激通过基于耦合振荡器的钙库夹带引起全局起搏器活动。L型钙通道引起的膜电位变化和正反馈以产生更多的钙库活动是这一过程的基础，它在钙库振荡器之间提供了远程电化学耦合。我们得出结论，淋巴管起搏是由活性钙库之间基于耦合振荡器的相互作用介导的。它们通过钙库激活剂的细胞间和细胞内扩散进行弱耦合，并通过膜电位进行强耦合。基于钙库的起搏预计发生在以下细胞系统中：1）振荡性钙释放诱导去极化；2）膜去极化提供正反馈以诱导进一步的钙库钙释放；3）细胞相互连接。令人惊讶的是，包括胃肠道、淋巴管、尿道和血管组织以及心脏起搏器细胞在内的大量细胞系统都满足这些条件。
