Extracellular ATP and zinc are co-secreted with insulin and activate multiple P2X purinergic receptor channels expressed by islet beta-cells to potentiate insulin secretion
Extracellular ATP and zinc are co-secreted with insulin and activate multiple P2X purinergic receptor channels expressed by islet beta-cells to potentiate insulin secretion
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DOI：
10.1007/s11302-008-9126-y
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发表时间：
2008-12-01
影响因子：
3.5
通讯作者：
Schwiebert, Erik M.
中科院分区：
文献类型：
--
作者：
Richards-Williams, Clintoria;Contreras, Juan L.;Schwiebert, Erik M.
众所周知，细胞外葡萄糖浓度升高时，胰岛β细胞(β细胞)会与胰岛素和锌共同分泌三磷酸腺苷。尽管有这些知识，但细胞外分泌的三磷酸腺苷和锌的生理作用尚不清楚。我们假设分泌的ATP和锌是自分泌的嘌呤能信号分子，激活β细胞表达的P2X嘌呤能受体(P2XR)通道，促进葡萄糖刺激的胰岛素分泌(GSIS)。为了验证这一假设，我们在“实时”分析中对固定时间点的胰岛素分泌进行了ELISA法检测，并证实生理性胰岛素促分泌剂葡萄糖刺激细胞外环境与原代大鼠胰岛的胰岛素一起分泌三磷酸腺苷和锌。外源性三磷酸腺苷和锌单独或联合作用也能诱导胰岛素的分泌。最重要的是，细胞外ATP清除剂、锌螯合剂和P2受体拮抗剂的存在可减弱GSIS。此外，在永生化的β细胞和原代胰岛中，表达了一组独特的P2XR通道亚型，即P2X(2)、P2X(3)、P2X(4)和P2X(6)的mRNA和蛋白，每个亚型都被细胞外ATP门控，并被细胞外锌正向调节。在这些结果的基础上，我们认为在内分泌胰岛内，分泌的ATP和锌通过ATP门控和锌调节的P2XR通道对胰岛素的分泌具有深刻的自分泌调节作用。
It is well established that ATP is co-secreted with insulin and zinc from pancreatic beta-cells (beta-cells) in response to elevations in extracellular glucose concentration. Despite this knowledge, the physiological roles of extracellular secreted ATP and zinc are ill-defined. We hypothesized that secreted ATP and zinc are autocrine purinergic signaling molecules that activate P2X purinergic receptor (P2XR) channels expressed by beta-cells to enhance glucose-stimulated insulin secretion (GSIS). To test this postulate, we performed ELISA assays for secreted insulin at fixed time points within a "real-time" assay and confirmed that the physiological insulin secretagogue glucose stimulates secretion of ATP and zinc into the extracellular milieu along with insulin from primary rat islets. Exogenous ATP and zinc alone or together also induced insulin secretion in this model system. Most importantly, the presence of an extracellular ATP scavenger, a zinc chelator, and P2 receptor antagonists attenuated GSIS. Furthermore, mRNA and protein were expressed in immortalized beta-cells and primary islets for a unique subset of P2XR channel subtypes, P2X(2), P2X(3), P2X(4), and P2X(6), which are each gated by extracellular ATP and modulated positively by extracellular zinc. On the basis of these results, we propose that, within endocrine pancreatic islets, secreted ATP and zinc have profound autocrine regulatory influence on insulin secretion via ATP-gated and zinc-modulated P2XR channels.