Critical role of ATP-induced ATP release for Ca2+ signaling in nonsensory cell networks of the developing cochlea
Critical role of ATP-induced ATP release for Ca2+ signaling in nonsensory cell networks of the developing cochlea
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DOI：
10.1073/pnas.1616061113
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发表时间：
2016-11-15
影响因子：
11.1
通讯作者：
Mammano, Fabio
中科院分区：
文献类型：
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作者：
Ceriani, Federico;Pozzan, Tullio;Mammano, Fabio
胞质游离钙浓度（[Ca 2 +]（c））的时空协调变化在多种组织中起着至关重要的作用。在哺乳动物耳蜗的发育中的感觉上皮中，细胞外三磷酸腺苷浓度（[ATP]（e））的升高触发[Ca 2 +]（c）振荡和细胞间肌醇1，4，5-三磷酸（IP 3）依赖性Ca 2+波的传播。尚不确定的是间隙连接通道和连接蛋白半通道对这些基本机制的相对贡献，这些缺陷会损害听力获得。另一个相关的开放性问题是[Ca 2 +]（c）振荡是否需要该系统中胞质IP 3浓度（[IP 3]（c））的振荡。为了解决这些问题，我们进行了Ca 2+成像实验，在小上皮嵴的小鼠耳蜗出生后第5天左右，并构建了一个计算模型，定量坚持实验数据。我们的结果表明，在[ATP]（e）的实验范围内，[Ca ~（2+）]（c）振荡由Hopf型分岔控制，而不需要[IP ~ 3]（c）振荡。该模型准确地复制的空间范围和传播速度的细胞间的Ca 2+波，并预测ATP诱导的ATP释放的Ca 2+信号的细胞间传播的主要机制。该模型还揭示了一个不连续的过渡，从传播制度（细胞间Ca 2+波速度> 11 μ m.s（-1））传播失败（速度= 0），这发生在降低最大ATP释放速率低于最小阈值。这里提出的方法克服了由于缺乏特异性连接蛋白通道抑制剂的主要限制，并可以扩展到其他耦合细胞系统。
Spatially and temporally coordinated variations of the cytosolic free calcium concentration ([Ca2+](c)) play a crucial role in a variety of tissues. In the developing sensory epithelium of the mammalian cochlea, elevation of extracellular adenosine trisphosphate concentration ([ATP](e)) triggers [Ca2+](c) oscillations and propagation of intercellular inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ waves. What remains uncertain is the relative contribution of gap junction channels and connexin hemichannels to these fundamental mechanisms, defects in which impair hearing acquisition. Another related open question is whether [Ca2+](c) oscillations require oscillations of the cytosolic IP3 concentration ([IP3](c)) in this system. To address these issues, we performed Ca2+ imaging experiments in the lesser epithelial ridge of the mouse cochlea around postnatal day 5 and constructed a computational model in quantitative adherence to experimental data. Our results indicate that [Ca2+](c) oscillations are governed by Hopf-type bifurcations within the experimental range of [ATP](e) and do not require [IP3](c) oscillations. The model replicates accurately the spatial extent and propagation speed of intercellular Ca2+ waves and predicts that ATP-induced ATP release is the primary mechanism underlying intercellular propagation of Ca2+ signals. The model also uncovers a discontinuous transition from propagating regimes (intercellular Ca2+ wave speed > 11 mu m.s(-1)) to propagation failure (speed = 0), which occurs upon lowering the maximal ATP release rate below a minimal threshold value. The approach presented here overcomes major limitations due to lack of specific connexin channel inhibitors and can be extended to other coupled cellular systems.