Institute of Biomedicine, University of Eastern Finland, FI-70211 Kuopio, Finland
Institute of Biomedicine, University of Eastern Finland, FI-70211 Kuopio, Finland.
Biochem J. 2018 May 24;475(10):1755-1772. doi: 10.1042/BCJ20180054.
Extracellular nucleotides are used as signaling molecules by several cell types. In epidermis, their release is triggered by insults such as ultraviolet radiation, barrier disruption, and tissue wounding, and by specific nerve terminals firing. Increased synthesis of hyaluronan, a ubiquitous extracellular matrix glycosaminoglycan, also occurs in response to stress, leading to the attractive hypothesis that nucleotide signaling and hyaluronan synthesis could also be linked. In HaCaT keratinocytes, ATP caused a rapid and strong but transient activation of hyaluronan synthase 2 () expression via protein kinase C-, Ca/calmodulin-dependent protein kinase II-, mitogen-activated protein kinase-, and calcium response element-binding protein-dependent pathways by activating the purinergic P2Y receptor. Smaller but more persistent up-regulation of and , and delayed up-regulation of were also observed. Accumulation of peri- and extracellular hyaluronan followed 4-6 h after stimulation, an effect further enhanced by the hyaluronan precursor glucosamine. AMP and adenosine, the degradation products of ATP, markedly inhibited expression and, despite concomitant up-regulation of and , inhibited hyaluronan synthesis. Functionally, ATP moderately increased cell migration, whereas AMP and adenosine had no effect. Our data highlight the strong influence of adenosinergic signaling on hyaluronan metabolism in human keratinocytes. Epidermal insults are associated with extracellular ATP release, as well as rapid up-regulation of /, , and hyaluronan synthesis, and we show here that the two phenomena are linked. Furthermore, as ATP is rapidly degraded, the opposite effects of its less phosphorylated derivatives facilitate a rapid shut-off of the hyaluronan response, providing a feedback mechanism to prevent excessive reactions when more persistent signals are absent.
细胞外核苷酸被多种细胞类型用作信号分子。在表皮中，它们的释放是由紫外线辐射、屏障破坏和组织损伤以及特定的神经末梢放电等刺激触发的。透明质酸（一种普遍存在的细胞外基质糖胺聚糖）的合成增加也会对压力做出反应，这就产生了一个有吸引力的假设，即核苷酸信号和透明质酸合成也可能相关。在 HaCaT 角质形成细胞中，ATP 通过蛋白激酶 C、Ca/钙调蛋白依赖性蛋白激酶 II、丝裂原活化蛋白激酶和钙反应元件结合蛋白依赖性途径激活嘌呤能 P2Y 受体，迅速而强烈但短暂地激活透明质酸合酶 2 () 的表达。还观察到 和 的较小但更持久的上调，以及 的延迟上调。刺激后 4-6 小时，细胞外和细胞周围透明质酸的积累随之而来，而透明质酸前体氨基葡萄糖进一步增强了这种作用。ATP 的降解产物 AMP 和腺苷显著抑制 的表达，尽管 和 的表达同时上调，但抑制了透明质酸的合成。功能上，ATP 适度增加了细胞迁移，而 AMP 和腺苷则没有影响。我们的数据突出了腺苷能信号对人角质形成细胞中透明质酸代谢的强烈影响。表皮刺激与细胞外 ATP 的释放以及 / 、 和透明质酸合成的快速上调有关，我们在这里表明这两种现象是相关的。此外，由于 ATP 迅速降解，其磷酸化程度较低的衍生物的相反作用促进了透明质酸反应的快速关闭，为当不存在更持久的信号时提供了一种防止过度反应的反馈机制。
