P2 receptor networks regulate signaling duration over a wide dynamic range of ATP concentrations
P2 receptor networks regulate signaling duration over a wide dynamic range of ATP concentrations
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DOI：
10.1242/jcs.122705
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发表时间：
2013-08-15
影响因子：
4
通讯作者：
Dixon, S. Jeffrey
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文献类型：
--
作者：
Grol, Matthew W.;Pereverzev, Alexey;Dixon, S. Jeffrey
原始细胞间信号分子 ATP 通过细胞表面 P2 受体的两个家族发挥作用 - G 蛋白偶联受体的 P2Y 家族和配体门控阳离子通道的 P2X 家族。多种 P2 受体在多种细胞类型中表达。然而，这些受体网络在任何生物系统中的重要性仍然未知。使用成骨细胞作为模型系统，我们发现低浓度的 ATP（10 μM，ATP（低））会诱导胞质 Ca2+ 短暂升高，而高浓度 ATP（1 mM，ATP（高））会引起更持续的升高。此外，Ca2+信号在 ATP 浓度范围（1 nM 至 1 mM）显着数百万倍范围内实现了分级增加。接下来，我们证明了ATP（低）引起Ca2+调节转录因子NFATc1的短暂核定位；而 ATP（高）则引发更持续的定位。当用 ATP（高）刺激时，P2X7 功能丧失小鼠的成骨细胞仅表现出短暂的 Ca2+-NFATc1 信号传导；相反，在野生型细胞中观察到持续的信号传导。其他实验揭示了 P2Y 受体在介导低 ATP 浓度诱导的瞬时信号传导中的作用。因此，对 ATP 具有不同亲和力的不同 P2 受体解释了对细胞外核苷酸的广泛敏感性。最后，ATP（高）而非 ATP（低）被证明能够引发 NFAT 靶基因 Ptgs2（编码 COX-2）的稳健表达，这与 Ca2+-NFAT 信号传导持续时间在调节靶基因表达中的关键作用一致。总而言之，P2 受体群提供了一种机制，细胞可以通过该机制在较宽的浓度范围内感知 ATP，并将这种输入转导为不同的细胞信号。
The primordial intercellular signaling molecule ATP acts through two families of cell-surface P2 receptors - the P2Y family of G-protein-coupled receptors and the P2X family of ligand-gated cation channels. Multiple P2 receptors are expressed in a variety of cell types. However, the significance of these networks of receptors in any biological system remains unknown. Using osteoblasts as a model system, we found that a low concentration of ATP (10 mu M, ATP(low)) induced transient elevation of cytosolic Ca2+, whereas a high concentration of ATP (1 mM, ATP(high)) elicited more sustained elevation. Moreover, graded increases in the Ca2+ signal were achieved over a remarkable million-fold range of ATP concentrations (1 nM to 1 mM). Next, we demonstrated that ATP(low) caused transient nuclear localization of the Ca2+-regulated transcription factor NFATc1; whereas, ATP(high) elicited more sustained localization. When stimulated with ATP(high), osteoblasts from P2X7 loss-of-function mice showed only transient Ca2+-NFATc1 signaling; in contrast, sustained signaling was observed in wild-type cells. Additional experiments revealed a role for P2Y receptors in mediating transient signaling induced by low ATP concentrations. Thus, distinct P2 receptors with varying affinities for ATP account for this wide range of sensitivity to extracellular nucleotides. Finally, ATP(high), but not ATP(low), was shown to elicit robust expression of the NFAT target gene Ptgs2 (encoding COX-2), consistent with a crucial role for the duration of Ca2+-NFAT signaling in regulating target gene expression. Taken together, ensembles of P2 receptors provide a mechanism by which cells sense ATP over a wide concentration range and transduce this input into distinct cellular signals.