Characteristics and Control of Ductular Secretion

In this section we consider how the pancreatic ductular cells contribute to the flow and composition of pancreatic juice in the postprandial period. The ducts of the pancreas can be considered the effector arm of a pH regulatory system designed to respond to luminal acid in the small intestine and secrete just enough bicarbonate to restore pH to neutrality (Fig. 29-3). This regulatory function also requires mechanisms to sense luminal pH and convey this information to the pancreas, as well as other epithelia (e.g., biliary ductules and the duodenal epithelium itself) capable of secreting bicarbonate. The pH-sensing mechanism is embodied in specialized endocrine cells localized within the small intestinal epithelium, known as S cells. When luminal pH falls below approximately 4.5, S cells are triggered to release secretin, presumably in response to protons. The components of this regulatory loop constitute a self-limited system. Thus, as secretin evokes secretion of bicarbonate, pH in the small intestinal lumen will rise and the signal for release of secretin from S cells will be terminated.

Figure 29-3 Participation of secretin and HCO₃⁻ secretion in a classic negative-feedback loop that responds to a fall in luminal pH in the duodenum.

At the cellular level, secretin directly stimulates epithelial cells to secrete bicarbonate ions into the ductular lumen, with water following via the paracellular route to maintain osmotic equilibrium. Secretin increases cAMP in the ductular cells and thereby opens CFTR Cl⁻ channels (Fig. 29-4) and causes an outflow of Cl⁻ into the duct lumen. This secondarily drives the activity of an adjacent antiporter that exchanges the chloride ions for bicarbonate. There is also emerging evidence that CFTR itself may be permeable to some extent to bicarbonate ions when opened. In either case, the bicarbonate secretory process is dependent on CFTR, which provides a rationale for the defects in pancreatic function that are seen in the disease of cystic fibrosis, in which CFTR is mutated. The bicarbonate needed for this secretory process is derived from two sources. Some is taken up across the basolateral membrane of the ductular epithelial cells via the symporter NBC-1 (for sodium-bicarbonate cotransporter type 1). Recall that the process of gastric acid secretion results in an increase in circulating bicarbonate ions, which can serve as a source of bicarbonate to be secreted by the pancreas. However, bicarbonate can also be generated intracellularly via the activity of the enzyme carbonic anhydrase. The net effect is to move HCO₃⁻ into the lumen and thereby increase pH and the volume of pancreatic juice.

Figure 29-4 Ion transport pathways in pancreatic duct cells. CA, carbonic anhydrase; CFTR, cystic fibrosis transmembrane conductance regulator; NBC-1, sodium/bicarbonate cotransporter (symporter) type 1; NHE-1, sodium-hydrogen exchanger (antiporter) type 1.

Characteristics and Control of Acinar Secretion

In contrast to the pancreatic ductules, where secretin is the most important physiological agonist, CCK plays the predominant role at the level of the acinar cells. Thus, it is important to understand how release of CCK is controlled during the small intestinal phase of the response to a meal.

CCK is the product of I cells, which are also localized to the small intestinal epithelium. These classic enteroendocrine cells release CCK into the interstitial space when specific food components are present in the lumen, particularly free fatty acids and certain amino acids. Release of CCK from I cells may occur as a result of a direct interaction of fatty acids or amino acids, or both, specifically with the I cells themselves. Release of CCK is also regulated by two luminally acting releasing factors that can stimulate the I cell. The first of these, referred to as CCK-releasing factor (or peptide), is secreted by paracrine cells within the epithelium into the small intestinal lumen, probably in response to products of fat or protein digestion (or both). The second releasing factor, likewise a peptide, is called monitor peptide and is released by pancreatic acinar cells into pancreatic juice. Both CCK-releasing factor and monitor peptide can also be released in response to neural input, which is probably particularly important in initiating pancreatic secretion during the cephalic and gastric phases, thereby preparing the system to digest the meal as soon as it enters the small intestine.

What is the significance of these peptide-releasing factors? Their primary role appears to be to match CCK release, as well as the resulting availability of pancreatic enzymes, to the need for these enzymes to digest the meal in the small intestinal lumen (Fig. 29-5). Because the releasing factors are peptides, they will be subject to proteolytic degradation by enzymes such as pancreatic trypsin in exactly the same way as dietary protein. However, when dietary protein is ingested, it is present in much greater amounts in the lumen than the releasing factors and thus “competes” with the releasing factors for proteolytic degradation. The net effect is that the releasing factors will be protected from breakdown while the meal is in the small intestine and are therefore available to continue stimulation of CCK release from I cells. However, once the meal has been digested and absorbed, the releasing factors are degraded and the signal for release of CCK is shut off.

Figure 29-5 Mechanisms responsible for controlling the release of cholecystokinin (CCK) from duodenal I cells. ACh, acetylcholine; CCK-RP, CCK-releasing peptide; GRP, gastrin-releasing peptide. Solid arrows represent stimulatory effects, whereas dashed arrows indicate inhibition.

Redrawn from Barrett KE: Gastrointestinal Physiology. New York, McGraw-Hill, 2006.)

CCK evokes secretion by pancreatic acinar cells in two ways. First, it is a classic hormone that travels through the bloodstream to encounter acinar cell CCK1 receptors. However, CCK also stimulates neural reflex pathways that impinge on the pancreas. Vagal afferent nerve endings in the wall of the small intestine are responsive to CCK by virtue of their expression of CCK1 receptors. As described earlier for the effect of CCK on gastric emptying, binding of CCK activates a vagovagal reflex that can further enhance acinar cell secretion via activation of pancreatic enteric neurons and release of a series of neurotransmitters such as acetylcholine, gastrin-releasing peptide, and vasoactive intestinal polypeptide (VIP).

The secretory products of pancreatic acinar cells are largely presynthesized and stored in granules that cluster toward the apical pole of acinar cells (Fig. 29-6). The most potent stimuli of acinar cell secretion, including CCK itself, acetylcholine, and gastrinreleasing peptide, act by mobilizing intracellular Ca⁺⁺. Stimulation of acinar cells results in phosphorylation of a series of regulatory and structural proteins within the cell cytosol that serve to move the granules closer to the apical membrane, where fusion of granule and plasma membranes can occur. The contents of the granule are then discharged into the acinar lumen and subsequently washed out of the pancreas by an exudate of plasma crossing the tight junctions linking the acinar cells together and ultimately by ductular secretions. In the period between meals, in contrast, the granule constituents are resynthesized by the acinar cells and then stored until needed to digest the next meal. The signals that mediate granule resynthesis are less well understood, but resynthesis may be stimulated by the same agonists that evoke the initial secretory response.

Figure 29-6 Receptors of the pancreatic acinar cell and regulation of secretion. The block arrow indicates that Ca⁺⁺-dependent signaling pathways play the most prominent role. ACh, acetylcholine; CCK, cholecystokinin; GRP, gastrin-releasing peptide; VIP, vasoactive intestinal polypeptide.

Redrawn from Barrett KE: Gastrointestinal Physiology. New York, McGraw-Hill, 2006.)