Rückl Martin, Parker Ian, Marchant Jonathan S, Nagaiah Chamakuri, Johenning Friedrich W, Rüdiger Sten
Institut für Physik, Humboldt-Universität zu Berlin, Berlin, Germany.
Departments of Neurobiology and Behavior, Physiology and Biophysics, University of California, Irvine, Irvine, California, United States of America.
PLoS Comput Biol. 2015 Jan 8;11(1):e1003965. doi: 10.1371/journal.pcbi.1003965. eCollection 2015 Jan.
The oscillating concentration of intracellular calcium is one of the most important examples for collective dynamics in cell biology. Localized releases of calcium through clusters of inositol 1,4,5-trisphosphate receptor channels constitute elementary signals called calcium puffs. Coupling by diffusing calcium leads to global releases and waves, but the exact mechanism of inter-cluster coupling and triggering of waves is unknown. To elucidate the relation of puffs and waves, we here model a cluster of IP3R channels using a gating scheme with variable non-equilibrium IP3 binding. Hybrid stochastic and deterministic simulations show that puffs are not stereotyped events of constant duration but are sensitive to stimulation strength and residual calcium. For increasing IP3 concentration, the release events become modulated at a timescale of minutes, with repetitive wave-like releases interspersed with several puffs. This modulation is consistent with experimental observations we present, including refractoriness and increase of puff frequency during the inter-wave interval. Our results suggest that waves are established by a random but time-modulated appearance of sustained release events, which have a high potential to trigger and synchronize activity throughout the cell.
细胞内钙浓度的振荡是细胞生物学中集体动力学最重要的例子之一。通过肌醇1,4,5-三磷酸受体通道簇进行的局部钙释放构成了称为钙瞬变的基本信号。钙的扩散耦合导致全局释放和波，但簇间耦合和波触发的确切机制尚不清楚。为了阐明钙瞬变与波的关系，我们在此使用具有可变非平衡IP3结合的门控方案对IP3R通道簇进行建模。混合随机和确定性模拟表明，钙瞬变不是具有恒定持续时间的刻板事件，而是对刺激强度和残余钙敏感。随着IP3浓度的增加，释放事件在几分钟的时间尺度上受到调制，重复的波状释放夹杂着几个钙瞬变。这种调制与我们提出的实验观察结果一致，包括不应期和波间间隔期间钙瞬变频率的增加。我们的结果表明，波是由持续释放事件的随机但时间调制的出现建立的，这些事件具有触发和同步整个细胞活动的高潜力。
