Petit Pierre, Lajoix Anne-Dominique, Gross René
Montpellier I University and CNRS UMR 5232, Centre for Pharmacology and Innovation in Diabetes, Montpellier, France.
Eur J Pharm Sci. 2009 May 12;37(2):67-75. doi: 10.1016/j.ejps.2009.01.007. Epub 2009 Jan 30.
Extracellular adenosine triphosphate is able to modulate pancreatic beta-cell function, acting on P2 purinergic ionotropic (P2X) and metabotropic (P2Y) receptors. Physiologically, ATP entrains beta-cells into a common rhythm by coordinating Ca(2+) oscillations; it plays a central role in insulin secretion pulsatility. ATP also triggers a positive feedback signal amplifying glucose-induced insulin release, which argues for a potential pharmacological application. ATP has consistently been shown to increase cytoplasmic free calcium concentration, notably in human tissue. Acting on P2X receptors, of which different molecular subtypes are expressed in beta-cells, it leads to a transient insulin release that may involve a closure of K(ATP) channels or a rapidly decaying inward current. Activation of G-protein-coupled P2Y receptors triggers different signalling pathways and amplifies insulin release in a glucose-dependent way. It has recently been shown that pancreatic beta-cells express different molecular subtypes of receptors, which may explain the complex interaction of P2Y ligands on high- and low-affinity binding sites. Despite the complexity of this purinergic pharmacology, consistent pre-clinical data suggest the potential of P2Y receptor agonists as drug candidates for type 2 diabetes.
细胞外三磷酸腺苷能够调节胰腺β细胞功能，作用于P2嘌呤能离子型（P2X）和代谢型（P2Y）受体。在生理状态下，ATP通过协调Ca(2+)振荡使β细胞进入共同节律；它在胰岛素分泌的脉冲性中起核心作用。ATP还触发一个正反馈信号，放大葡萄糖诱导的胰岛素释放，这表明其具有潜在的药理学应用价值。ATP一直被证明可增加细胞质游离钙浓度，尤其是在人体组织中。作用于β细胞中表达的不同分子亚型的P2X受体时，它会导致短暂的胰岛素释放，这可能涉及ATP敏感性钾通道的关闭或快速衰减的内向电流。G蛋白偶联的P2Y受体的激活触发不同的信号通路，并以葡萄糖依赖的方式放大胰岛素释放。最近有研究表明，胰腺β细胞表达不同分子亚型的受体，这可能解释了P2Y配体在高亲和力和低亲和力结合位点上的复杂相互作用。尽管这种嘌呤能药理学很复杂，但一致的临床前数据表明P2Y受体激动剂作为2型糖尿病候选药物的潜力。
