Proteolytic degradation of releasing factors, such as those involved in the release of CCK, occurs in the small intestine due to enzymes like pancreatic trypsin. However, the presence of dietary protein in larger amounts in the intestine competes with the releasing factors for proteolytic degradation, thus protecting the releasing factors. Once the meal is digested and absorbed, the releasing factors are degraded, leading to the shutdown of the signal for CCK release.

CCK stimulates secretion by pancreatic acinar cells through both hormonal and neural reflex pathways. It acts as a hormone, traveling through the bloodstream to interact with CCK1 receptors on acinar cells. Additionally, CCK stimulates neural reflex pathways that affect the pancreas. Vagal afferent nerve endings in the small intestine express CCK1 receptors and respond to CCK. The binding of CCK activates a vagovagal reflex, which further enhances acinar cell secretion through the activation of pancreatic enteric neurons. This, in turn, leads to the release of neurotransmitters like acetylcholine, gastrin-releasing peptide, and vasoactive intestinal polypeptide (VIP).

Pancreatic acinar cells store their secretory products in granules clustered near the apical pole of the cells. The secretion of acinar cells, including CCK, acetylcholine, and gastrin-releasing peptide (GRP), is primarily stimulated by mobilizing intracellular calcium ions. Stimulation of acinar cells results in the phosphorylation of various regulatory and structural proteins within the cytosol, causing the granules to move closer to the apical membrane. Subsequently, the granules fuse with the plasma membrane, releasing their contents into the acinar lumen. These contents are then washed out by plasma exudate and ductular secretions. Between meals, acinar cells resynthesize the granule constituents in preparation for the digestion of the next meal, which can be stimulated by the same agonists that initially triggered the secretory response.

Bile, another important digestive juice, mixes with the meal in the small intestine. It is produced by the liver and aids in the digestion and absorption of lipids. Bile is stored and concentrated in the gallbladder before being released in response to meal ingestion. The contraction of the gallbladder and relaxation of the sphincter of Oddi are primarily evoked by CCK.
Fig. 30.5 ). 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.
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 •Fig. 30.6 Receptorsofthepancreaticacinarcellandregulationofsecretion.ThethickblackarrowindicatesthatCa++-dependentsignalingpathwaysplaythemostprominentrole.ACh,acetylcholine;CCK,cholecystokinin;GRP,gastrin-releasingpeptide;VIP,vasoactiveintestinalpolypeptide;M3,M3muscarinicreceptor;CCK-1;CCKreceptortype1.(RedrawnfromBarrettKE.Gastrointestinal Physiology. NewYork:McGraw-Hill;2006.) 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. 30.6 ). The most potent stimuli of acinar cell secretion, including CCK, acetylcholine, and gastrin-releasing peptide (GRP), 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 move the granules closer to the apical membrane, where the granules fuse with the plasma membrane. The contents of the granule are then discharged into the acinar lumen and washed out by an exudate of plasma crossing the tight junctions, linking the acinar cells together, and subsequently by ductular secretions. In the period between meals the granule constituents are resynthesized by the acinar cells and then stored until needed to digest the next meal. Resynthesis may be stimulated by the same agonists that evoke the initial secretory response.
Another important digestive juice that is mixed with the meal in the small intestinal lumen is bile. Bile is produced by the liver, and the mechanisms that are involved, as well as the specific constituents, will be discussed in greater detail in when we address the transport and metabolic functions of the liver. However, for purposes of the current discussion, bile is a secretion that serves to aid in digestion and absorption of lipids. Bile flowing out of the liver is stored and concentrated in the gallbladder until it is released in response to ingestion of a meal. Contraction of the gallbladder, as well as relaxation of the sphincter of Oddi, are evoked predominantly by CCK.