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Review
, 80, 473-506

Insulin Granule Biogenesis, Trafficking and Exocytosis

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Review

Insulin Granule Biogenesis, Trafficking and Exocytosis

June Chunqiu Hou et al. Vitam Horm.

Abstract

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 (Del Prato, 2003; Del Prato and Tiengo, 2001). 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 plasma membrane 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.

Figures

Figure 16.1
Figure 16.1
Insulin biogenesis: Preproinsulin is synthesized in rough endoplasmic reticulum (RER) and is converted to proinsulin. Proinsulin is later transported to Trans-Golgi Network (TGN) and packed into immature granule via sorting for entry. The immature granule loses the clathrin coating and other unwanted components through sorting by exit. In parallel, proinsulin is converted to insulin and condensation/crystallization (sorting by retention) occurs. These processes account for the maturation of the immature insulin granules into a mature insulin secretory granule following TGN exit.
Figure 16.2
Figure 16.2
Signaling pathway: Glucose, the major stimulant, via glycolysis and mitochondrial ATP energy production increases the ATP/ADP ratio that leads to the closure of the ATP-sensitive K+ (KATP) channels. The subsequent cellular depolarization activates voltage dependent calcium channels resulting in extracellular Ca2+ influx and fusion of insulin granules with the plasma membrane. The incretin hormone GLP-1 acts on its receptor at β cell plasma membrane to activate adenylyl cyclase and increase intracellular cAMP levels. In turn, cAMP binds and activates protein kinase A and EPAC. EPAC then functions to increase intracellular calcium level from intracellular calcium stores in the endoplasmic reticulum and to increase the number of readily releasable pool of insulin granules at the plasma membrane. The combination of these two processes results in a potentiation of insulin secretion.

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