Insulin granule biogenesis, trafficking and exocytosis.
Insulin granule biogenesis, trafficking and exocytosis.
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DOI：
10.1016/s0083-6729(08)00616-x
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发表时间：
2009
影响因子：
--
通讯作者：
Pessin, Jeffrey E.
中科院分区：
文献类型：
--
作者：
Hou, June Chunqiu;Min, Le;Pessin, Jeffrey E.
越来越明显的是，导致胰岛素分泌异常的β细胞功能障碍是患者从葡萄糖耐量受损状态发展为明显的2型糖尿病的基本因素。虽然大量的研究已经检查了胰岛素颗粒生物合成、分选和胞吐的分子、细胞和生理机制，但控制这些过程的精确机制及其在糖尿病发展中的失调仍然是重要的研究领域。我们现在知道胰岛素生物合成起始于粗面内质网中前胰岛素原的合成和前胰岛素原向胰岛素原的转化。胰岛素原开始被包装在高尔基体网络中，并被分选成未成熟的分泌颗粒。这些未成熟的颗粒通过ATP依赖性质子泵变成酸性，胰岛素原经历蛋白水解裂解，导致胰岛素和C肽的形成。在颗粒成熟过程中，胰岛素与锌和钙以致密核心颗粒的形式结晶，并且不需要的货物和膜蛋白经历选择性逆行运输到用于分泌的组成性运输途径或降解途径。新形成的成熟致密核心胰岛素颗粒填充两个不同的细胞内池，即易释放池（RRP）和储备池。这两种不同的群体被认为是胰岛素释放的双相性质的原因，其中RRP颗粒与质膜相关，并经历急性钙依赖性释放，导致第一相胰岛素分泌。相比之下，第二相胰岛素分泌需要将保留的颗粒池运输到质膜。胰岛素颗粒与质膜融合的初始触发是细胞内钙的升高，并且在葡萄糖刺激的情况下，由ATP产生增加、ATP敏感性钾通道的关闭和细胞去极化引起。反过来，这打开了电压依赖性钙通道，允许增加细胞外钙的流入。钙被认为与融合调节蛋白突触球蛋白的成员结合，突触球蛋白在功能上抑制融合抑制蛋白复合蛋白。复合蛋白和突触融合蛋白以及几种其他调节蛋白与核心融合机制相互作用，核心融合机制由质膜中的Q-或t-SNARE蛋白syntaxin 1和SNAP 25组成，质膜与胰岛素颗粒中的R-或v-SNARE蛋白VAMP 2组装。在本章中，我们将回顾目前的进展，胰岛素颗粒的生物合成，分选，运输，胞吐和信号转导途径，构成葡萄糖依赖性胰岛素分泌的分子基础。
It is becoming increasingly apparent that beta cell dysfunction resulting in abnormal insulin secretion is the essential element in the progression of patients from a state of impaired glucose tolerance to frank type 2 diabetes. Although extensive studies have examined the molecular, cellular and physiologic mechanisms of insulin granule biogenesis, sorting, and exocytosis the precise mechanisms controlling these processes and their dysregulation in the developed of diabetes remains an area of important investigation. We now know that insulin biogenesis initiates with the synthesis of preproinsulin in rough endoplastic reticulum and conversion of preproinsulin to proinsulin. Proinsulin begins to be packaged in the Trans-Golgi Network and is sorting into immature secretory granules. These immature granules become acidic via ATP-dependent proton pump and proinsulin undergoes proteolytic cleavage resulting the formation of insulin and C-peptide. During the granule maturation process, insulin is crystallized with zinc and calcium in the form of dense-core granules and unwanted cargo and membrane proteins undergo selective retrograde trafficking to either the constitutive trafficking pathway for secretion or to degradative pathways. The newly formed mature dense-core insulin granules populate two different intracellular pools, the readily releasable pools (RRP) and the reserved pool. These two distinct populations are thought to be responsible for the biphasic nature of insulin release in which the RRP granules are associated with the plasma membrane and undergo an acute calcium-dependent release accounting for first phase insulin secretion. In contrast, second phase insulin secretion requires the trafficking of the reserved granule pool to the plasma membrane. The initial trigger for insulin granule fusion with the plasma membrane is a rise in intracellular calcium and in the case of glucose stimulation results from increased production of ATP, closure of the ATP-sensitive potassium channel and cellular depolarization. In turn, this opens voltage-dependent calcium channels allowing increased influx of extracellular calcium. Calcium is thought to bind to members of the fusion regulatory proteins synaptogamin that functionally repressors the fusion inhibitory protein complexin. Both complexin and synaptogamin interact as well as several other regulatory proteins interact with the core fusion machinery composed of the Q- or t-SNARE proteins syntaxin 1 and SNAP25 in the plasmamembrane that assembles with the R- or v-SNARE protein VAMP2 in insulin granules. In this chapter we will review the current progress of insulin granule biogenesis, sorting, trafficking, exocytosis and signaling pathways that comprise the molecular basis of glucose-dependent insulin secretion.