Ježek Petr, Holendová Blanka, Jabůrek Martin, Tauber Jan, Dlasková Andrea, Plecitá-Hlavatá Lydie
Department of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences, 14220 Prague, Czech Republic.
Antioxidants (Basel). 2021 Jan 29;10(2):197. doi: 10.3390/antiox10020197.
Pancreatic β-cell insulin secretion, which responds to various secretagogues and hormonal regulations, is reviewed here, emphasizing the fundamental redox signaling by NADPH oxidase 4- (NOX4-) mediated HO production for glucose-stimulated insulin secretion (GSIS). There is a logical summation that integrates both metabolic plus redox homeostasis because the ATP-sensitive K channel (K) can only be closed when both ATP and HO are elevated. Otherwise ATP would block K, while HO would activate any of the redox-sensitive nonspecific calcium channels (NSCCs), such as TRPM2. Notably, a 100%-closed K ensemble is insufficient to reach the -50 mV threshold plasma membrane depolarization required for the activation of voltage-dependent Ca channels. Open synergic NSCCs or Cl channels have to act simultaneously to reach this threshold. The resulting intermittent cytosolic Ca-increases lead to the pulsatile exocytosis of insulin granule vesicles (IGVs). The incretin (e.g., GLP-1) amplification of GSIS stems from receptor signaling leading to activating the phosphorylation of TRPM channels and effects on other channels to intensify integral Ca-influx (fortified by endoplasmic reticulum Ca). ATP plus HO are also required for branched-chain ketoacids (BCKAs); and partly for fatty acids (FAs) to secrete insulin, while BCKA or FA β-oxidation provide redox signaling from mitochondria, which proceeds by HO diffusion or hypothetical SH relay via peroxiredoxin "redox kiss" to target proteins.
本文综述了胰腺β细胞对各种促分泌剂和激素调节作出反应的胰岛素分泌，重点阐述了烟酰胺腺嘌呤二核苷酸磷酸氧化酶4（NOX4）介导的过氧化氢（HO）产生的基本氧化还原信号传导在葡萄糖刺激的胰岛素分泌（GSIS）中的作用。存在一种逻辑总和，它整合了代谢和氧化还原稳态，因为ATP敏感性钾通道（K）只有在ATP和HO都升高时才能关闭。否则，ATP会阻断K，而HO会激活任何氧化还原敏感的非特异性钙通道（NSCC），如瞬时受体电位阳离子通道M2（TRPM2）。值得注意的是，100%关闭的K集合不足以达到激活电压依赖性钙通道所需的-50 mV阈值质膜去极化。开放的协同NSCC或氯通道必须同时作用才能达到该阈值。由此产生的间歇性胞质钙增加导致胰岛素颗粒囊泡（IGV）的脉冲式胞吐作用。肠促胰岛素（如胰高血糖素样肽-1，GLP-1）对GSIS的放大作用源于受体信号传导，导致TRPM通道磷酸化激活，并对其他通道产生影响，以增强整体钙内流（由内质网钙增强）。支链酮酸（BCKA）分泌胰岛素也需要ATP加HO；脂肪酸（FA）分泌胰岛素部分需要ATP加HO，而BCKA或FA的β氧化提供来自线粒体的氧化还原信号，该信号通过HO扩散或经由过氧化物酶体氧化还原蛋白“氧化还原亲吻”的假设性硫氢基团中继传递给靶蛋白。
