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Pandol SJ. The Exocrine Pancreas. San Rafael (CA): Morgan & Claypool Life Sciences; 2010.

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The Exocrine Pancreas.

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Digestive Enzymes

DIGESTIVE ENZYME SYNTHESIS AND TRANSPORT

The acinar cell of the exocrine pancreas has the greatest rate of protein synthesis of any mammalian organ. The acinar cell has a highly developed endoplasmic reticulum (ER) system combined with mechanisms to modify and transport newly synthesized proteins through the secretory pathway (Figure 6) [2, 26]. In addition to its functions in performing protein synthesis and processing, the ER is the major storage site for intracellular calcium, which, when released into the cytoplasm, is the mediator of regulated secretion of stored digestive enzymes into the pancreatic ductal system [27].

FIGURE 6. Electron micrograph of the pancreatic acinar cell.

FIGURE 6

Electron micrograph of the pancreatic acinar cell. This electron micrograph shows the key cellular structures involved in synthesis, processing and storage of digestive enzymes. On the left is the rough endoplasmic reticulum; in the middle is the Golgi (more...)

Each protein synthesized in the ER must undergo specific secondary modifications as well as folding in order for it to be properly transported to destination organelles, such as Golgi, zymogen granule (storage for the digestive enzymes) and lysosome or membrane sites. The zymogen granule stores digestive enzymes and are released by exocytosis with neurohumoral stimulation with a meal as described below. Also, the systems for both protein synthesis and processing must be able to adapt because of the variation in the demand for protein synthesis as a function of diet and because protein processing in the ER could be adversely affected by environmental factors, such as alcohol, smoking, altered metabolism and xenobiotics.

Synthesis of digestive enzymes takes place in the internal space of the rough endoplasmic reticulum (RER) (Figure 7). The mechanism for translation of the cell's messenger RNA (mRNA) into exportable protein is explained by the signal hypothesis [28, 29]. The main feature of the hypothesis is that ribosomal subunits attach to mRNA and initiate synthesis of a hydrophobic “signal” sequence on the NH2-terminal of nascent proteins. This complex then attaches to the outer surface of the endoplasmic reticulum, and the signal sequence targets the protein being synthesized into the lumen of the RER.

FIGURE 7. The signal hypothesis mechanism of protein synthesis.

FIGURE 7

The signal hypothesis mechanism of protein synthesis. The endoplasmic reticulum is the site of new protein synthesis. The mechanism of protein synthesis is initiated with the attachment of a messenger RNA (mRNA) to ribosomal subunits. As illustrated, (more...)

Newly synthesized proteins can undergo modifications in the endoplasmic reticulum, including disulfide bridge formation, phosphorylation, sulfation and glycosylation. Conformational changes resulting in tertiary and quaternary structures of the protein also take place in the endoplasmic reticulum. Processed proteins from the endoplasmic reticulum are transported to the Golgi complex where further posttranslational modification (glycosylation) and concentration occur [30].

The Golgi complex also serves the important function of sorting and targeting newly synthesized proteins into various cell compartments (Figure 6). Digestive enzymes are transported to the zymogen granules [30]. Lysosomal hydrolases are sorted to the lysosome [31]. For this lysosomal pathway, mannose-6-phosphate groups are added to oligosaccharide chains on the protein during its presence in the cis-Golgi complex. The mannose-6-phosphate groups serve as a recognition site for a specific receptor. The interaction of the lysosomal enzyme mannose-6-phosphate with its receptor leads to formation of vesicles that transport this complex to the lysosome, delivering the enzyme. In the lysosome, the enzyme dissociates from the receptor, which in turn cycles back to the Golgi complex.

Secretion of the digestive enzymes occurs by exocytosis. Exocytosis consists of movement of the secretory granule to the apical surface, the recognition of a plasma membrane site for fusion, and the fission of the granule membrane/plasma membrane site after fusion [2, 32]. Roles for actin–myosin, SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein [SNAP] receptor) proteins and guanosine triphosphate (GTP)-binding proteins have been demonstrated to participate in the exocytosis processes [3340]. Intracellular signals generated by agonist receptors as discussed below interact with these entities to mediate digestive enzyme secretion via exocytosis of zymogen granules.

ENVIRONMENTAL AND GENETIC STRESSORS AND THE SECRETORY PATHWAY

As indicated above, proteins enter the ER as unfolded polypeptides that require further processing for activation and targeting to the appropriate organelle or membrane site. In this transport, the ER and other organelles along the secretory pathway are faced with several challenges in completing these functions with high fidelity. Figure 8 illustrates many of these challenges, which are often referred to as ER stress in many organs including the exocrine pancreas. At the bottom of the figure, the unfolded protein response (UPR) that results from the stressors and mediates an adaptive response so that the exocrine pancreas can adjust its machinery to the effects of the stressors and proceed with normal synthetic and transport functions is indicated. The types of both genetic and environmental insults depicted here are the ones that are known to be ER stressors in general [41]. For the exocrine pancreas, in particular, the machinery must adapt to increased protein loads requiring processing during and after a meal as the pancreas replenishes its stores of digestive enzymes. This increased load would require synthesis of chaperones and foldases, as well as upregulation of the systems involved in degradation of unfolded and misfolded proteins. The quality control system to degrade these unusable proteins called ER-associated protein degradation (ERAD) is required to rid the cell from accumulation of permanently misfolded and unfolded proteins that are toxic to the cell.

FIGURE 8. Pancreatic ER stress the unfolded protein response.

FIGURE 8

Pancreatic ER stress the unfolded protein response. The figure shows several types of factors that could promote ER stress in the pancreatic acinar cell. These include increased protein folding demand, insufficient ER chaperone and foldase function, mutant (more...)

There are several genetic and environmental stressors illustrated in Figure 8 that occur in the pancreas that are likely ER stressors requiring the acinar cell to activate its adaptive UPR or face the possibility of cellular pathologies. For example, mutations in key protease digestive enzymes are known to lead to chronic forms of pancreatitis and increased rate of pancreatic cancer [42]. A recent report [43], in fact, demonstrates that a mutation in human cationic trypsinogen causes ER stress in pancreatic cells suggesting that the chronic form of pancreatitis occurring in patients with this mutation occurs because the UPR is insufficiently robust to adjust to the ER stress caused by the mutation.

Other stressors encountered by the exocrine pancreatic acinar cell UPR and shown in Figure 8 include alcohol, smoking, metabolic disorders and xenobiotics as well as reactive oxygen species (ROS). Except for information on the genetic mutation discussed above and recent work on alcohol abuse [44], there is little information on these factors affecting the pancreas and ER stress and whether pathology results from an insufficiently robust UPR. Alcohol abuse and smoking are key risk factors in the epidemiology of the major diseases of the exocrine pancreas, pancreatitis and pancreatic cancer [17, 45, 46]. Recent epidemiologic studies demonstrate that smoking accelerates the development of pancreatitis in alcoholic patients and may have an additive or multiplicative effect when combined with alcohol to cause pancreatitis [45, 47]. An important and unexplained observation is that only a small proportion of heavy drinkers/smokers develop pancreatic diseases [48]. Although the reason for lack of development of pathology in the majority of those who drink and smoke is unknown, it is likely that the exocrine pancreas adapts to the environmental stressors with a robust UPR preventing cellular pathology in most individuals. Inability to adapt completely may lead to cellular pathologies.

EXOCRINE PANCREATIC UPR ADAPTIVE RESPONSE

The adaptive UPR has three major functions [41, 4952]. These include: 1) an upregulation of the expression and function of chaperones and foldases to augment the folding and export capacity of the ER; 2) activation of the ER-associated protein degradation (ERAD) system to rid the ER of accumulated unfolded and misfolded proteins; and 3) a global reduction in translation of mRNA to decrease the processing demand for newly synthesized proteins. Under severe and prolonged stress that exceeds to its adaptive capacity, the UPR can initiate cell death programs.

Figure 9 presents an overview of UPR, showing that there are three main sensor–transducers located in the membrane of the ER [41, 49]. They are inositol-requiring protein-1 (IRE1), activating transcription factor-6 (ATF6) and protein kinase RNA (PKR)-like ER kinase (PERK). In each case, the transmembrane sensor–transducer measures the ER luminal environment as well as the folding status of the proteins there and transmits this information across the ER membrane. In some cases, the transmembrane sensor–transducer is “silenced” by binding of an ER chaperone called immunoglobulin-binding protein (BiP) to its luminal domain. ER stress unfolded and misfolded proteins compete for binding BiP, resulting in removing its “silencing” effect and in activation of the sensor. This represents one way for activation of sensor–transducers. However, there are likely many other mechanisms that have yet to be determined.

FIGURE 9. The participants of the unfolded protein response.

FIGURE 9

The participants of the unfolded protein response. The figure shows the three main sensor/transducers of the unfolded response, inositol-requiring protein-1 (IRE1), activating transcription factor-6 (ATF6) and protein kinase RNA (PKR)-like ER kinase (PERK). (more...)

Activation of the IRE1sensor–transducer initiates a response to increase the expression of ER chaperones and foldases to assist in protein folding and transport (Figure 9). The mechanism of sensing stress involves IRE1 homodimerization and trans-autophosphorylation to activate a specific RNAse activity that it carries. IRE1 RNAse cleaves the mRNA for unspliced X-box binding protein1 (XBP1). Activated IRE1 removes a 26-nucleotide intron from XBP1 resulting in an mRNA that translates into a potent transcription factor called spliced XBP1 (XBP1-S) [5355]. XBP1-S, in turn, binds to ER stress element (ERSE) and the UPR element (UPRE) DNA binding sites to upregulate many UPR target genes, such as the chaperones BiP and GRP94 and the gene encoding XBP1-U [5356]. This ability to increase transcription of XBP1 leads to more substrates for expression of the XBP1-S transcription factor, thus, augmenting this protective response. The IRE1/XBP1 pathway also leads to increased expression of foldases, such as protein disulfide isomerase (PDI), enzymes for lipid synthesis for expanding the ER membrane and ER capacity, components of the ER-associated degradation (ERAD), all protective mechanisms to adapt the system to the stress [56].

ATF6 is another ER transmembrane protein that responds to ER stress (Figure 9). The C-terminal luminal domain is sensitive to ER stress, while the N-terminal cytoplasmic domain contains a DNA transcription-activating domain. Release of BiP binding that occurs as BiP alternatively binds to unfolded proteins during ER stress allows ATF6 transport to the Golgi compartment where it is cleaved by site-1 and site-2 proteases (sp1/sp2) to a 50–60 kDa fragment that migrates to the nucleus to activate transcription of XBP1 and other UPR target genes [57]. This shows a coordinated effort between the IRE1 and ATF6 pathways to mediate an adaptive ER protective response utilizing XBP1.

As indicated, XBP1-S is a potent transcription activator for many UPR target genes including the molecular chaperone BiP. The increased expression would allow more BiP available to inactivate the ER sensors. Thus, BiP acts as a luminal sensor of unfolded proteins as well as the regulator of mechanisms to initiate the protective UPR, including the production of sufficient BiP to attenu-ate an ER stress response.

PERK plays a key role in adjusting the cell to ER stress by causing a significant attenuation of general protein synthesis (Figure 9). The activation of PERK by autophosphorylation (Thr980) leads to its phosphorylation of the alpha subunit of the eukaryotic translation initiation factor-2α (eIF-2α) [57, 58]. The nonphosphorylated form of eIF-2α in its GTP-bound form is essential for translation initiation because it recruits the first tRNA (tRNAMET) to the ribosomal subunits to start translation of the attached mRNA. Phosphorylation of eIF2α at Ser51 by PERK blocks eIF2α-mediated initiation, resulting in a general inhibition of protein synthesis. Cells with genetic deletion of PERK or cells containing eIF2α with position 51 containing alanine instead of serine to prevent phosphorylation do not attenuate protein synthesis with ER stress [59, 60]. As a consequence, cells are more sensitive to ER stress. This shows that general inhibition of protein synthesis by the PERK signaling pathway is another key way where the pancreas can adapt to stress responses. Persistent phosphorylation of eIF2α leads to specific translational upregulation of activating transcription factor 4 (ATF4) that targets genes involved in antioxidant effects including synthesis of glutathione [61]. ATF4 also upregulates the expression of the transcription factor C/EBP homologous protein (CHOP) which induces apoptosis [62]. This last pathway shows how a high level of sustained ER stress can lead to pathologic consequences that results when the adaptive responses are insufficiently robust to attenuate the stress posed on the protein synthesis and transport mechanisms.

ENVIRONMENTAL STRESS AND DISEASES OF THE EXOCRINE PANCREAS

The most common diseases of the exocrine pancreas are pancreatitis and pancreatic cancer. Alcohol abuse and smoking are key risk factors in the epidemiology of both diseases [17, 45, 46]. In the case of alcohol abuse, the increased risk for pancreatic cancer occurs largely through the effect of alcohol abuse causing chronic forms of pancreatitis [63]. Smoking also contributes to the development of pancreatitis and is a major risk factor for pancreatic cancer independent of pancreatitis [17, 46, 63]. Recent epidemiologic studies demonstrate that smoking accelerates the development of pancreatitis in alcoholic patients and may have an additive or multiplicative effect when combined with alcohol to cause pancreatitis [45, 47]. The mechanisms underlying the effects of alcohol and smoking on the development of pancreatic diseases are incompletely understood. An important and unexplained observation is that only a small proportion of heavy drinkers/smokers develop pancreatic diseases [48]. Although the reason for lack of development of pathology in the majority of those who drink and smoke is unknown, we hypothesize that an adaptive UPR is sufficiently robust in most individuals to prevent pathology.

DIGESTIVE ENZYMES AND THEIR FUNCTIONS

The human pancreas has the largest capacity for protein synthesis of any organ in the human body. Much of the capacity is devoted to synthesis of the digestive enzymes that are secreted in the intestinal lumen. Table 1 lists the major proteolytic, amylolytic, lipolytic and nuclease digestive enzymes [6466]. Some of the enzymes are present in more than one form (e.g., cationic trypsinogen, anionic trypsinogen and mesotrypsinogen). Further, they are capable of digesting the cell and causing significant damage. There are mechanisms to prevent these enzymes from potentially digesting the pancreas including storage and packing in acidic zymogen granules to inhibit activity; and synthesis and storage as inactive precursor forms. The lists in Table 1 show some of the enzymes that are stored in the pancreas before secretion as inactive proenzymes. These proenzymes are activated when they enter the duodenum. As illustrated in Figure 10, activation of these enzymes takes place in the surface of the duodenal lumen, where a brush-border glycoprotein peptidase, enterokinase, activates trypsinogen by removing (by hydrolysis) an N-terminal hexapeptide fragment of the molecule (Val–Asp–Asp–Asp–Asp–Lys) [6567]. The active form, trypsin, then catalyzes the activation of the other inactive proenzymes. Of note, many key digestive enzymes, such as α-amylase and lipase, are present in the pancreas in their active forms (Table 1). Presumably, these enzymes would not cause pancreatic cellular damage if released into the pancreatic cell/tissue because there is no starch, glycogen or triglyceride substrate for these enzymes in pancreatic tissue.

TABLE 1. Digestive proenzymes and enzymes in the pancreas. Digestive enzymes are stored in the pancreas as either inactive proenzyme forms or active enzymes.

TABLE 1

Digestive proenzymes and enzymes in the pancreas. Digestive enzymes are stored in the pancreas as either inactive proenzyme forms or active enzymes.

FIGURE 10. Intestinal digestive enzyme activation.

FIGURE 10

Intestinal digestive enzyme activation. Inactive proenzymes called zymogens enter the duodenum where enterokinase which is attached to the intestinal surface ally enzymatic leaves trypsinogen activating it to trypsin. Trypsin, in turn, converts zymogens (more...)

Another mechanism that the exocrine pancreas utilizes to prevent intracellular activation involves the synthesis and incorporation of a trypsin inhibitor (pancreatic secretory trypsin inhibitor [PSTI]) into the secretory pathway and zymogen granule. PSTI is a 56-amino acid peptide that inactivates trypsin by forming a relatively stable complex with the enzyme near its catalytic site [68]. The function of the inhibitor is to inactivate trypsins that are formed autocatalytically in the pancreas or pancreatic juice, thus, preventing pancreatic digestion and resulting disorders, such as pancreatitis [69, 70]. In the following paragraphs are descriptions of the functions of the major digestive enzymes.

Amylase is secreted by both the pancreas and salivary glands, differing in molecular weight, carbohydrate content and electrophoretic mobility [71]. However, they have identical enzyme activities. Salivary amylase initiates digestion in the mouth and may account for a significant portion of starch and glycogen digestion because it is transported with the meal into the stomach and small intestine, where it continues to have activity. Optimal enzyme activity occurs at neutral pH. During a meal, gastric pH can approach neutrality despite gastric acid secretion because of the buffering from molecules in the meal as well as alkaline secretions from the salivary glands and gastric mucus. Salivary amylase can contribute up to 50% of starch and glycogen digestion while pancreatic amylase contributes the remainder. The action of both salivary and pancreatic amylase is to hydrolyze 1,4-glycoside linkages at every other junction between carbon 1 and oxygen. The products of amylase digestion are maltose and maltotriose (2- and 3-α-1,4-linked molecules, respectively) and α-dextrins containing 1,6-glycosidic linkages because 1,6-glycosidic linkages in starch cannot be hydrolyzed by amylase. The brush-border enzymes complete the hydrolysis of the products of amylase digestion to glucose. The final product, glucose, is transported across the intestinal absorptive epithelial cell by a Na+-coupled transport [72, 73].

Lipases are secreted mainly by the pancreas in contrast to amylase where there is a significant salivary contribution. There are lingual and gastric lipases but these contribute to fat digestion in only a minor fashion. Major lipases secreted by the pancreas are lipase (or triglyceride lipase) and prophospholipases (Table 1).

Pancreatic lipase hydrolyzes a triglyceride molecule to two fatty acid molecules released from carbons 1 and 3 and a monoglyceride with a fatty acid esterified to glycerol at carbon 2 [74]. Lipase binds to the oil/water interface of the triglyceride oil droplet, where it acts to hydrolyze the triglyceride. Both bile acids and colipase are important for the full activity of lipase. Bile acids aid in the emulsification of triglyceride to enlarge the surface area for lipase to act on, and they form micelles with fatty acids and monoglyceride, which, in turn, remove these products from the oil/water interface. Colipase is believed to form a complex with lipase and bile salts. This ternary complex anchors lipase and allows it to act in a more hydrophilic environment on the hydrophobic surface of the oil droplet.

Phospholipase catalyzes the hydrolysis of the fatty acid ester linkage at carbon 2 of phosphatidylcholine [66]. This cleavage leads to the formation of free fatty acid and lysophosphatidylcholine.

Proteases secreted by the pancreas are generally divided into two groups—the endopeptidases and the exopeptidases (Figure 11). All are stored and secreted from the pancreas as inactive proforms that are activated in the duodenum by trypsin. Trypsin, chymotrypsin and elastase are endopeptidases that cleave specific peptide bonds adjacent to specific amino acids within a protein. Exopeptidases include carboxypeptidases that cleave peptide bonds at the carboxyl terminus of proteins.

FIGURE 11. Classification of proteases.

FIGURE 11

Classification of proteases. This graphic presents two major types of proteases, the exopeptidases that cleave peptide bonds releasing one amino acid at a time from the NH2 or COOH terminal ends of a protein; and the endopeptidases that cleave peptide (more...)

Importantly, the combined actions of the pancreatic proteases and pepsin from the stomach result in the formation of oligopeptides and free amino acids. The oligopeptides are further digested by brush-border enzymes on the lumenal surface of the small intestine. Both free amino acids and oligopeptides are transported across the intestinal mucosa by a group of Na+- and H+-coupled transporters [75]. It is interesting that only certain amino acids (mostly essential amino acids) and oligopeptides can be measured in the lumen during digestion, indicating that the combined action of the proteases is not random and that the products result from the combined specificities of the individual proteases. These amino acids have greater effects on stimulating pancreatic secretion, inhibiting gastric emptying, regulating small bowel motility and causing satiety. Thus, the specific pattern of protease actions leads to the physiologic regulation of several organs in the gastrointestinal tract.

REGULATION OF DIGESTIVE ENZYME SYNTHESIS

The mechanisms involved in regulating expression of digestive enzymes in the exocrine pancreas have been partially elucidated. The investigations have addressed the following two questions: First, what accounts for the specific expression of digestive enzymes in the pancreas? Second, how do alterations in dietary nutrients change the synthesis of specific digestive enzymes? Genes for digestive enzymes, such as amylase, chymotrypsin and elastase, contain enhancer regions in their 5' flanking nucleotide sequences that regulate the transcription of their mRNAs, termed the pancreas consensus element (PCE) [7678]. A transcription factor, PTF-1, is present selectively in the exocrine pancreas, binds to this region and is essential for expression of these digestive enzymes [7782]. Thus, PTF-1 represents at least one of the differentiation-regulated factors that accounts for digestive enzyme expression in the pancreas.

Numerous studies have demonstrated that the relative synthesis rates of specific digestive enzymes change as a function of dietary intake. For example, a carbohydrate-rich diet results in an increase in synthesis of amylase and a decrease in that of chymotrypsinogen [83]; a lipid-rich diet enhances lipase expression [84]; and an alcohol-rich diet decreases amylase expression [85]. The mechanisms responsible for this adaptation are only partially understood. The regulation occurs at the level of gene transcription in many of these conditions [85]. Several studies have also demonstrated that amylase gene expression is regulated by both insulin and diet [83].

STIMULATION OF DIGESTIVE ENZYME SECRETION FROM THE ACINAR CELL

Digestive enzymes synthesized and stored in the zymogen granule are available for transport and release into the lumen of the pancreatic acinus and transport through the pancreatic ductal system into the intestine. The transport and release of zymogen granule contents occurs through exocytosis [2]. In vitro preparations of acinar cells from the pancreas of small animals have been used extensively to determine the mechanisms of regulation of exocytosis and digestive enzyme secretion (Figure 12). The results using animal pancreatic tissue have been confirmed in part using preparations of human pancreatic acinar cells [86].

FIGURE 12. Regulation of exocytosis.

FIGURE 12

Regulation of exocytosis. Digestive enzymes are stored in zymogen granules at the apical surface of the acinar cell. Regulated secretion occurs through exocytosis stimulated by neurohumoral agents. These agents include gastrin-releasing peptide (GRP), (more...)

Functional receptors that mediate digestive enzyme secretion have been identified for cholecystokinin (CCK), acetylcholine, gastrin-releasing peptide (GRP), substance P, vasoactive intestinal peptide (VIP) and secretin in preparations of pancreatic acinar cells from several species by measuring responses to ligands specific for the receptors and using radiolabelled ligand binding studies [87]. Furthermore, the molecular structure for each of these receptor types has been elucidated from cloning and sequencing [88]. Each is a G-protein-coupled receptor (GPCR) with seven hydrophobic domains believed to be membrane-spanning segments. The receptors are on the basolateral plasma membrane of the acinar cell.

The GPCRs on the acinar cells have been divided into two groups according to their mechanisms of stimulating secretion (Figure 12). In one category are GPCRs for each the neurotransmitter VIP and the hormone secretin. The interaction of each of these agonists with their specific GPCRs on acinar cells leads to activation of adenylate cyclase and a rise in cellular cAMP, which in turn activates enzyme secretion through cAMP-dependent protein kinase A [89]. In the other group are GPCRs for the neurotransmitter acetylcholine, GRP and substance P and the hormone CCK. Interaction of each agonist in this group with its specific GPCR causes secretion through the phosphoinositide-calcium signaling system [3, 27]. The agonist–receptor interaction for these receptors leads to a phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate to 1,2-diacylglycerol and inositol 1,4,5-triphosphate (IP3). IP3, in turn, releases calcium from endoplasmic reticulum stores. The calcium release into the cytosol causes a rapid rise in the concentration of free calcium ([Ca+2]i) that is necessary for the secretory response. With physiologic concentrations of agonists, the increase in [Ca+2]i initiates in the apical area of acinar cell in the vicinity of the zymogen granules followed by a propagated “wave” toward the basolateral area of the cell [9093]. Also, the increases in [Ca+2]i are transient giving an oscillatory pattern. Each spike in [Ca+2]i leads to a “burst” in zymogen granule exocytosis and secretion. Calcium release into the cytosol is also mediated by ryanodine receptors and signals interacting with the ryanodine receptor, such as calcium and fatty acid-coenzyme A esters [94]. Other intracellular signaling molecules involved in intracellular calcium release are cyclic adenosine diphosphate (ADP)-ribose and nicotinic acid adenine dinucleotide phosphate (NAADP) [27]. These messengers are involved in propagating and regulating the “waves” and “oscillations” that are essential to the physiologic calcium signaling that mediates secretion.

The mechanisms by which increases in [Ca+2]i mediate secretion are not established but involve calmodulin-dependent protein kinases and actin–myosin interactions, SNARE proteins and guanosine triphosphate-binding proteins, as discussed earlier [87]. The continued stimulation of enzyme secretion by these agents also depends on the influx of extracellular calcium [95]. This influx is regulated by changes in nitric oxide and cyclic guanosine monophosphate (cGMP) [96]. The components of the plasma membrane calcium influx channel have been determined and involved [97, 98, 99].

The digestive enzyme secretory response may also be regulated by 1,2-diacylglycerol, protein kinase C and arachidonic acid [100, 101]. Specific phosphorylations and dephosphorylations of cellular proteins also occur with both cAMP agonists and calcium-phosphoinositide agonists [3]. The exact roles of these events in secretion are not established.

The enzyme secretory response of the acinar cell to a combination of an agonist that acts through cAMP and an agonist that acts through changes in calcium is greater than the sum of the individual responses. An example of such a combination would be VIP or secretin with acetylcholine. The exact mechanism of this potentiated response is not known, but it functions physiologically so that significant quantities of secretion occur with a combination of small increases in individual agonists.

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