Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6465-70. doi: 10.1073/pnas.0908935107. Epub 2010 Mar 22.
Extracellular ATP has been proposed as a paracrine signal in rodent islets, but it is unclear what role ATP plays in human islets. We now show the presence of an ATP signaling pathway that enhances the human beta cell's sensitivity and responsiveness to glucose fluctuations. By using in situ hybridization, RT-PCR, immunohistochemistry, and Western blotting as well as recordings of cytoplasmic-free Ca(2+) concentration, Ca(2+), and hormone release in vitro, we show that human beta cells express ionotropic ATP receptors of the P2X(3) type and that activation of these receptors by ATP coreleased with insulin amplifies glucose-induced insulin secretion. Released ATP activates P2X(3) receptors in the beta-cell plasma membrane, resulting in increased Ca(2+) and enhanced insulin secretion. Therefore, in human islets, released ATP forms a positive autocrine feedback loop that sensitizes the beta cell's secretory machinery. This may explain how the human pancreatic beta cell can respond so effectively to relatively modest changes in glucose concentration under physiological conditions in vivo.
细胞外 ATP 已被提议作为啮齿动物胰岛中的旁分泌信号，但不清楚 ATP 在人胰岛中起什么作用。我们现在表明存在一种 ATP 信号通路，可增强人胰岛β细胞对葡萄糖波动的敏感性和反应性。通过原位杂交、RT-PCR、免疫组织化学和 Western blot 以及体外细胞质游离 Ca(2+)浓度、Ca(2+)和激素释放的记录，我们表明人胰岛β细胞表达离子型 ATP 受体 P2X(3)型，并且这些受体由与胰岛素共释放的 ATP 激活，可增强葡萄糖诱导的胰岛素分泌。释放的 ATP 激活β细胞质膜中的 P2X(3)受体，导致Ca(2+)增加和胰岛素分泌增强。因此，在人胰岛中，释放的 ATP 形成正的自分泌反馈环，使β细胞的分泌机制敏感化。这可以解释为什么人胰腺β细胞在体内生理条件下能够对葡萄糖浓度的相对较小变化做出如此有效的反应。
