4 EB. Chang and PS. Leung Another major component of the gastric phase is the stimulation of gastrin release by luminal nutrients, especially peptides and aromatic amino acids (phenylalanine and tryptophan). Their presence is somehow sensed by antral G cells, which are then stimulated to release gastrin. In addition, these Iuminal agents appear to activate afferent enteric neurons that initiate reflex neural networks stimulating G- cell secretion, In contrast to protein hydrolysates, carbohydrates and fats are not potent stimuli of gastric acid secretion. The intestinal phase (Fig. 3.8c) is that component of gastric acid secretion stimulated by the presence of food in the small intestine. Itis the least important of the various phases, accounting for less than 10 % of total gastric acid secretion. The recognized initiators of this intestinal phase are distention and the digestion products of protein. Part of the humoral mechanism of the intestinal phase is probably due to absorbed amino acids, since intravenous administration of amino acids does stimulate gastric acid secretion, The intestinal phase by itself is a weak stimulus of gastric acid secretion but does appear to strongly potentiate the effects of histamine and gastrin, Inhibitory Mechanisms of Gastric Acid Secretion In each phase of the gastric response to meals, factors inhibit the acid secretion that accompanies stimulatory events. They play an important role in providing negative feedback to control the magnitude of the secretory response and in eventually bringing the stomach back to its resting state during interdigestive periods. Inhibition in the cephalic phase can be demonstrated by injection of bombesin, calcitonin, neurotensin, interleukin-1 (IL-1), prostaglandins, ot corticotropin- releasing factor (CRF) into the brain. Their inhibitory effects appear to be mediated by vagal and sympathetic fibers to the stomach, During the gastric phase, acidification in the antral mucosa inhibits gastrin release stimulated by sham feeding or by distention of the antrum, This effect is probably mediated by enteric neurons, as administration of atropine inhibits it. Increased luminal acid concentration also appears to stimulate the release of somatostatin from antral D cells, which inhibits gastrin release via a paracrine action. In the intestinal phase, three agents are known to inhibit acid secretion when instilled in the small intestine; they are acid, hyperosmolar solutions, and fat (the latter being most potent). The inhibition appears to be mediated by humoral substances collectively called “enterogastrones.” Although no agent has been definitively identified, the candidate hormones for enterogastrones include gastric inhibitory peptide (GIP), neurotensin, somatostatin, secretin, vasoactive intestinal peptide (VIP), enteroglucagon, and peptide YY. Of these, peptide YY is the most likely agent. It is released by fat from the distal small intestine and inhibits pentagastrin-stimulated acid secretion. In addition to these mechanisms, gastric secretion is also inhibited by secretin, gastrin releasing polypeptide (GRP), and cholecystokinin (CCK) (see Chap. 1).3. Gasttic Physiology 15 3 Pepsinogen Secretion Pepsin is an important digestive enzyme secreted predominantly from gastric chief cells in the form of pepsinogen, its precursor zymogen. These peptic cells are located on the walls of the oxyntic glands and appear to be regulated by many of the same agents involved in the regulation of gastric acid secretion Not surprisingly, therefore, pepsinogen secretion parallels that of acid secretion Agents such as gastrin, acetylcholine, CCK, and GIP stimulate pepsinogen release by increasing cytosolic Ca” through receptor-mediated phosphatidylinosi- tol metabolism (Fig. 3.9). Agents such as secretin, VIP, E-series of prostaglandins, and -adrenergic receptor agonists stimulate peptic cells by activating adenylate cyclase, resulting in the generation of CAMP and activation of a cAMP-dependent protein kinase. Both signal transduction pathways appear to stimulate the release of pepsinogen via exocytosis of secretory granules, but cAMP-mediated stimuli may also directly stimulate de novo synthesis of pepsinogen. On release into the lumen, pepsinogen is immediately activated by acid, with optimum pH being about 2. The formation of pepsin has a positive feedback effect, leading to a more rapid and complete conversion of pepsinogen into pepsin Fig. 3.10). Pepsin belongs to the general class of aspartic protease, so named because of the presence of two aspartic acid residues that are part of the catalytic site. It is a very good proteolytic enzyme and, because of its high activity on collagen, is more important for the digestion of meat than for vegetable protein. However, pepsin digestion of proteins is usually incomplete, since large peptides called peptones are Pepsinogen —— Calcium Stores ~ Membrane Membrane — Receptor Receptor Fig. 3.9 Regulation of pepsinogen secretion by gastric chief cells. Cellular mechanisms and ‘mediators involved in the action of regulatory agents of pepsinogen secretion illustrated above16 EB. Chang and PS. Leung Activation of Pepsinogen after its Release Active Pepsin Less Active Stimulated Pepsinogen pepsinogen N (+) N release in am fa c <———- Catalytic site | © Luminal 80 % by volume) is to secrete digestive enzymes responsible for our normal digestion, absorption and assimilation of nutri- ents, the endocrine pancreas (<2 % by volume) is to secrete islet peptide hormones for the maintenance of our glucose homeostasis. The pancreatic functions are finely regulated by neurocrine, endocrine, paracrine and/or intracrine mechanisms. Thus, dysregulation of these pathways should have significant impacts on our health and disease. Nevertheless, the underlying mechanisms by which pancreatic functions are regulated remain poorly understood. Embryologically, the human pancreas originates from two separate out- growths, designated as the dorsal and ventral buds, from the foregut endoderm directly posterior to the stomach; it is similar to the pancreas development in murine. The dorsal bud arises from evagination of the dorsal side of the primitive duodenum at around 3.75th week of gestation while the ventral bud arises from the base of the hepatic diverticulum at around 4.5th week of gestation. After undergoing the rotation of the ventral bud to the right of and then behind the developing EB. Chang, MD. (©) Department of Medicine, University of Chicago, Chicago, IL, USA e-mail: echang@medicine.bsd.uchicago.edu PS, Leung, Ph.D. (04) School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China e-mail: psleung @cuhk edu.hk PS. Leung (ed.), The Gastrointestinal System: Gastrointestinal, Nutritional 87 and Hepatobiliary Physiology, DOI 10.1007/978-94-017-8771-0_4, © Springer Science+Business Media Dordrecht 201488 EB. Chang and PS. Leung duodenal loop, the dorsal and ventral buds come into contact with one another and fusion of the two buds occurs at the end of 6th week of gestation. The ventral bud gives rise to the head and uncinate process of the pancreas while the dorsal bud forms the remaining portion of the organ. Meanwhile, the ventral bud duct is also fused with the distal portion of the dorsal bud duct and thus forms the subsequent duct of Wirsung, the main pancreatic duct which runs through the entire pancreas. The proximal portion of the dorsal bud duct becomes the future duct of Santorini, the accessory duct. During the fusion of the two pancreatic buds at 6th-7th week of gestation, the pancreatic architecture is observed with tubular structures surrounded by dense mesenchymal tissues next to the duodenal structure. The mesenchymal layer probably provides signals to the invading epithelium that regulates the balanced development of the future endocrine and exocrine portions of the pancreas. The dual origin of the organ accounts for the regional differences in the islet cell distribution in adult pancreas, In addition, the arterial blood supply of the pancreas arises from branches of the splenic, gastroduodenal and superior mesenteric arteries. Extrinsic neural innervation comes from both parasympathetic and sympathetic fibers through the splenic subdivisions of the celiac plexus. These nerves innervate all the major components of the pancreas, including blood vessels, pancreatic acinar cells, and duct and islet cells. 2 Digestive Enzyme Secretion of the Exocrine Pancreas 2.1 Synthesis and Exocytosis of Protein by the Pancreas Acinus as the Functional Unit of Exocrine Pancreas The major functional unit of the exocrine pancreas is the acinus or acini (in pleural), composed of contiguous, pyramid-shaped glandular cells with their apex facing the lumen of the acinus (Fig. 4.1). These cells have many noteworthy specialized features. First, they are highly polarized, having distinct functional and structural differences in the apical and basolateral plasma-membrane domains. Second, acinar cells have well developed Golgi and rough endoplasmic reticulum complexes, essential for the synthesis and storage of secretory proteins. Zymogen or storage granules can be also found in the apical (luminal side) cytoplasm of the cell, and they vary in number depending on the stage of development and state of stimulation by neuronal and hormonal agents. Nuclei are located at the very base of the cell. Mechanism of Protein Secretion by the A us The primary function of the pancreatic acinar cell is to produce large amounts of digestive enzyme proteins that are eventually transported through the ductal system into the duodenum to be mixed with intestinal chyme. The cellular events4 Pancreatic Physiology 89 Zymogen Granules Golgi Endoplasmic Reticulum Acinar Units Acinar Cell Fig. 4.1 A schematic diagram showing the structure and functional unit of the exocrine pancreas, The acinus is the functional unit of the exocrine pancreas, which is composed of contiguous pyramid-shaped glandular cells with their apex toward the lumen of the acinus. Acinar cells have well-developed Golgi and rough endoplasmic reticulum complexes, essential for synthesizing and storing large amounts of secretory proteins. Zymogens or storage granules can be found in the apical or Iuminal side of the cell Signal Endoplasmic Cistemnal_—_Peptidase Neche Reticulum Space Membrane Docking Protein Polysomes \ mRNA auc Initiation Codon Signal pony Signal Peptide Fig. 4.2 The processing and synthesis of pancreatic digestive enzymes. Proteins for export are first synthesized on polysomes attached to the outer or cytosolic aspect of the rough endoplasmic reticulum at the base of the acinar cell. As translation continues, the nascent protein transverses the endoplasmic reticulum membrane and enters the cisternal space involved in the synthesis and export of these proteins have been well-characterized Proteins for export are synthesized on polysomes attached to the outer or cytosolic aspect of the rough endoplasmic reticulum located at the base of the acinar cell. A special signal sequence after the AUG initiation codon is translated into an amino- terminal extension called the signal peptide (Fig. 4.2). The signal peptide is avidly90 EB. Chang and PS. Leung Fig. 4.3 The process of Membrane Membrane exocytosis of pancreatic Fusion Recycling enzyme secretion, After an appropriate neural or hormonal stimulus, zymogen granules move to apical membrane, fuse with plasma membrane, and discharge their contents into the luminal space by the process of exocytosis Secretion of Pancreatic Enzymes bound by a cytosolic protein called the signal-peptide recognition particle (SRP), which facilitates the binding of the mRNA-ribosomal complex to the endoplasmic reticulum (ER) membrane. It does so by recognizing and binding to a specific ER-membrane receptor or docking protein. Because of the hydrophobicity of the signal peptide, it enters the internal ER compartment. As translation continue: the rest of the protein traverses the ER membrane and enters the cisternal space. The signal peptide is then cleaved off by an enzyme called signal peptidase. The nascent protein then undergoes several post-translational modifications, including the formation of disulfide bridges, glycosylation, sulfation, and phosphorylation, Post-translational processing of secreting proteins is important in folding them into proper tertiary and quaternary configurations. Within 20-30 min of their synthesis, these proteins are transferred to the Golgi complex, where additional processing of the secretory proteins takes place. These modifications generally involve the removal of mannose groups from glycoproteins and progressive buildup toa complex glycosylated form by sequential additions of monosaccharides. These glycoproteins move from the cis to trans side of the Golgi complex and are eventually concentrated and packaged into storage granules. The secretory granules then move by an undefined mechanism to the apical portion of the acinar cell. Upon an appropriate neural of hormonal stimulus, zymogen granules move to the apical membrane, fuse with the plasma membrane, and discharge their contents into the luminal space by the process of exocytosis (Fig. 4.3) Regulation of Digestive Enzyme Secretion Several intracellular messengers appear to play a role in regulating the secretion of digestive enzymes. Increases in intracellular calcium are stimulated by agents such as cholecytokinin (CCK), acetylcholine, bombesin (gastrin-releasing peptide or GRP is the mammalian equivalent), and substance P. Although receptors on acinar cells for all these agents have been identified, it is likely that cholinergic muscarinic receptors are the major pathway for regulation (discussed below). These agents