The good and bad effects of cysteine S-nitrosylation and tyrosine nitration upon insulin exocytosis: a balancing act.
The good and bad effects of cysteine S-nitrosylation and tyrosine nitration upon insulin exocytosis: a balancing act.
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DOI：
10.2174/157339912800840514
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发表时间：
2012-07-01
影响因子：
3.3
通讯作者：
Thurmond DC
中科院分区：
文献类型：
--
作者：
Wiseman DA;Thurmond DC
随着对胰腺β细胞驱动和调节胰岛素分泌机制的了解不断加深，越来越多的证据表明，一氧化氮（NO）和其他密切相关的活性氮（RNS）在这一分泌过程中发挥着重要作用。NO和相关的RNS，特别是过氧亚硝酸盐，具有快速影响细胞内和细胞外隔室信号的能力，提供了非凡的信号传导潜力。已经确定一氧化氮通过激活鸟苷酸环化酶介导的环状GMP的产生。然而，复杂的细胞内氧化还原环境使人们相信•NO和过氧亚硝酸盐可能与更广泛的生物靶标相互作用，其中两种主要机制涉及1)半胱氨酸的s -亚硝基化，以及2)多种蛋白质中酪氨酸残基的硝化作用。旨在描述•NO和过氧亚硝酸盐在调节胰岛素分泌中的具体作用的努力表明，存在一个高度复杂和微妙的系统，有证据表明•NO和过氧亚硝酸盐可以在β细胞中以积极和消极的调节方式发挥作用。此外，β细胞内的最终生化结果，无论是否从给定的压力中补偿和恢复，可能是贡献信号和氧化还原状态的总和。这种看似调控的二分法为这些机制在糖尿病的发生和发展中发挥生理和病理生理作用提供了充分的机会。本文综述了最近积累的证据，指出一氧化氮诱导的翻译后修饰在β细胞胰岛素胞吐的正常调节和功能障碍中的作用。
As understanding of the mechanisms driving and regulating insulin secretion from pancreatic beta cells grows, there is increasing and compelling evidence that nitric oxide (•NO) and other closely-related reactive nitrogen species (RNS) play important roles in this exocytic process. •NO and associated RNS, in particular peroxynitrite, possess the capability to effect signals across both intracellular and extracellular compartments in rapid fashion, affording extraordinary signaling potential. It is well established that nitric oxide signals through activation of guanylate cyclase-mediated production of cyclic GMP. The intricate intracellular redox environment, however, lends credence to the possibility that •NO and peroxynitrite could interact with a wider variety of biological targets, with two leading mechanisms involving 1) S-nitrosylation of cysteine, and 2) nitration of tyrosine residues comprised within a variety of proteins. Efforts aimed at delineating the specific roles of •NO and peroxynitrite in regulated insulin secretion indicate that a highly-complex and nuanced system exists, with evidence that •NO and peroxynitrite can contribute in both positive and negative regulatory ways in beta cells. Furthermore, the ultimate biochemical outcome within beta cells, whether to compensate and recover from a given stress, or not, is likely a summation of contributory signals and redox status. Such seeming regulatory dichotomy provides ample opportunity for these mechanisms to serve both physiological and pathophysiologic roles in onset and progression of diabetes. This review focuses attention upon recent accumulating evidence pointing to roles for nitric oxide induced post-translational modifications in the normal regulation as well as the dysfunction of beta cell insulin exocytosis.