Membrane ©, Recycli
Exocytosis Plasma Membrane
Constitutive* Pathway Unregulated Secretion ^ • Proinsulin 1-2% Secretory Pathway -Membrane Proteins Regulated Secretion
• Pro insulin + Intermediates 4%
figure 7-18 Schematic diagram describing the synthesis and secretion of insulin. After the insulin mRNA leaves the nucleus, the translation process of preproinsulin occurs on the rough endoplasmic reticulum (RER). This is followed by rapid cleavage to proinsulin (within 1-2 min). Proinsulin is then released into the intracisternal spaces of the RER, where it folds and forms the native disulfide bonds of insulin. It is then transported to the Golgi apparatus by an energy-dependent process. The clathrin-coated early granules budding from the trans-Golgi cisternae are rich in proinsulin and contain the converting proteases, PC-2 and PC-3. Processing occurs mainly, if not exclusively, in the early secretory granules, giving rise to the more condensed mature granules. Fractionation studies have confirmed that the mature granule-dense cores almost entirely consist of insulin, often in crystalline arrays, whereas the granule-soluble phase that surrounds the inclusion mainly consists of C peptide and small amounts of proinsulin. The release of newly synthesized proinsulin and insulin begins only about 1 hr after synthesis in the RER, and hence granules must undergo a maturation process that renders them competent for secretion. There is no evidence for significant nongranular routes of secretion of either proinsulin or insulin in normal islets. Exocytosis of granules is regulated by glucose and many other factors and in humans and dogs results in the release of insulin and C peptide in equimolar proportions under both basal and stimulated conditions. [Modified with permission from Steiner, D. F,, Bell, G. I., Tager, H. S., and Rubenstein, A. H. (1995). Chemistry and biosynthesis of the isltet hormones: Insulin, islet amyloid polypeptide (amylin), glucagon, somatostatin and pancreatic polypeptide. In "Endocrinology" (L. DeGroot, M. Besser, H. G. Burger, J. L. Jameson, D. L. Loriaux, J. C. Marshall, W. D. Odell, J. T. Potts, Jr., and A. H. Rubenstein, eds.), 3rd ed„ Vol. 2, Chapter 76, pp. 1296-1328. W. B. Saunders Company, Philadelphia, PA.]
Major proglucagon fragment interdomain processing site signal peptide
Major proglucagon fragment interdomain processing site
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