Medical Physiology, 3rd Edition

Pancreatic Duct Cell

The pancreatic duct cell secretes isotonic NaHCO3

The principal physiological function of the pancreatic duct cell is to secrete an image-rich fluid that alkalinizes and hydrates the protein-rich primary secretions of the acinar cell. The apical step of transepithelial image secretion (Fig. 43-6) is mediated in part by a Cl-HCO3 exchanger, a member of the SLC26 family (see Table 5-4) that secretes intracellular image into the duct lumen. Luminal Cl must be available for this exchange process to occur. Although some luminal Cl is present in the primary secretions of the acinar cell, anion channels on the apical membrane of the duct cell provide additional Cl to the lumen in a process called Cl recycling. The most important of these anion channels is the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated Cl channel that is present on the apical membrane of pancreatic duct cells (see p. 120Box 43-1). Cl recycling is facilitated by the coactivation of CFTR and SLC26 exchangers through direct protein-protein interactions. In some species, such as the rat and mouse, pancreatic duct cells also contain a Ca2+-activated Cl channel on the apical membrane; this channel also provides Cl to the lumen for recycling. Apical Cl channels, including CFTR, may also directly serve as conduits for image movement from the duct cell to the lumen.

image

FIGURE 43-6 image secretion by the cells of the pancreatic duct. Secretin, via cAMP, phosphorylates and opens CFTR Cl channels. Exit of Cl through apical Cl channels depolarizes the basolateral membrane, generating the electrical gradient favoring electrogenic Na/HCO3 cotransport. CaM, calmodulin.

Box 43-1

Cystic Fibrosis

Cystic fibrosis (CF) is the most common lethal genetic disease in people of European descent, in whom it affects ~1 in 2000. Approximately 1 in 20 white individuals carry the autosomal recessive genetic defect. Clinically, CF is characterized by progressive pancreatic and pulmonary insufficiency resulting from the complications of organ obstruction by thickened secretions. The disease results from mutations in the CF gene (located on chromosome 7) that alter the function of its product, CFTR (see Fig 5-10). CFTR is a cAMP-activated Cl channel that is present on the apical plasma membrane of many epithelial cells. In the pancreas, CFTR has been localized to the apical membrane of duct cells, where it functions to provide the luminal Cl for Cl-HCO3 exchange (see Fig. 43-6).

Most CF gene mutations result in the production of a CFTR protein that is abnormally folded after its synthesis in the ER. The ER quality-control system recognizes these molecules as defective, and most mutant CFTR molecules are prematurely degraded before they reach the plasma membrane. Subsequent loss of CFTR expression at the plasma membrane disrupts the apical transport processes of the duct cell and results in decreased secretion of image and water by the ducts. As a result, protein-rich primary (acinar) secretions thicken within the duct lumen and lead to ductal obstruction and eventual tissue destruction. Pathologically, the ducts appear dilated and obstructed, and fibrotic tissue and fat gradually replace the pancreatic parenchyma—hence the original designation of cystic fibrosis. The subsequent deficiency of pancreatic enzymes that occurs leads to the maldigestion of nutrients and thus the excretion of fat in the stool (steatorrhea) by patients with CF. Before the development of oral enzyme replacement therapy, many patients with CF died of complications of malnutrition.

Now, the major cause of morbidity and mortality in CF is progressive pulmonary disease. The pathophysiology of lung disease in CF is more complex than that of pancreatic disease. A major finding is that the airway mucus is thick and viscous as a result of insufficient fluid secretion into the airway lumen. The pulmonary epithelium probably both secretes fluid (in a mechanism that requires CFTR) and absorbs fluid (in a mechanism that requires apical ENaC Na+ channels). In CF, the reduced activity of CFTR shifts the balance more toward absorption, and a thick mucous layer is generated that inhibits the ciliary clearance of foreign bodies (see p. 600). The results are an increased rate and severity of infections and thus inflammatory processes that contribute to the destructive process in the lung.

Pulmonary symptoms most commonly bring the patient to the physician's attention in early childhood. Cough and recurrent respiratory infections that are difficult to eradicate are usually the first indications of the illness. The child's sputum is particularly thick and viscous. Pulmonary function progressively declines over the ensuing years, and patients may also experience frequent and severe infections, atelectasis (collapse of lung parenchyma), bronchiectasis (chronic dilatation of the bronchi), and recurrent pneumothoraces (air in the intrapleural space). In addition to the pancreatic and pulmonary manifestations, CF also causes a characteristic increase in the [NaCl] of sweat, which is intermediate in heterozygotes. Pharmacological approaches that bypass the Cl-transport defect in a lung with CF are currently being evaluated, and considerable effort is being directed toward the development of in vivo gene-transfer techniques to correct the underlying genetic defect.

The intracellular image that exits the duct cell across the apical membrane arises from two pathways. imageN43-5 The first is direct uptake of image via an electrogenic Na/HCO3 cotransporter (NBCe1-B or SLC4A4; see p. 122), which presumably operates with an image stoichiometry of 1 : 2. The second mechanism is the generation of intracellular image from CO2 and OH, catalyzed by carbonic anhydrase (see p. 630).The OH in this reaction, along with H+, is derived from H2O. Thus, the H+ that accumulates in the cell must be extruded across the basolateral membrane. One mechanism of H+ extrusion is Na-H exchange. The second mechanism for H+ extrusion across the basolateral membrane, at least in some species, is an ATP-dependent H pump. Pancreatic duct cells contain acidic intracellular vesicles (presumably containing vacuolar-type H pumps) that are mobilized to the basolateral membrane of the cell after stimulation by secretin, a powerful secretagogue (see below). Indeed, H pumps are most active under conditions of neurohumoral stimulation. Thus, three basolateral transporters directly or indirectly provide the intracellular image that pancreatic duct cells need for secretion: (1) the electrogenic Na/HCO3cotransporter, (2) the Na-H exchanger, and (3) the H pump. The physiological importance of these three acid-base transporters in humans has yet to be fully established. The pancreatic duct cell accounts for ~75% of total pancreatic fluid secretion.

N43-5

image Secretion by the Pancreatic Duct

Contributed by Emile Boulpaep, Walter Boron

The current model for image secretion by the pancreatic duct is very similar to that outlined in Figure 43-6. However, we can now add some important details about the apical step of image secretion. The Cl-HCO3 exchanger at the apical membrane is a member of the SLC26 family (Mount and Romero, 2004)—previously known as the SAT family—specifically, SLC26A6 (also known as CFEX). We now appreciate that SLC26A6, which is capable of exchanging several different anions (e.g., Climage, oxalate), is electrogenic (Jiang etal, 2002). When mediating Cl-HCO3 exchange, it appears that SLC26A6 exchanges two image ions for every Cl ion. This stoichiometry would strongly favor the efflux of image across the apical membrane of the pancreatic duct cell.

As noted in the text, the Cl that enters the cell via SLC26A exits the cell via apical Cl channels, principally CFTR. Interestingly, it appears that an interaction between the SLC26A6 protein and CFTR greatly increases the open probability of CFTR (Ko etal, 2004).

Another member of the SLC26 family—SLC26A3—also is present in the apical membrane of pancreatic duct cells. SLC26A3 is also electrogenic but has a stoichiometry opposite to that of SLCA6, two Clions for every image. This transporter would extrude Cl (and take up image) from the duct cell across the apical membrane. Its physiological function might be to reabsorb image at times when the duct is not secreting image or to contribute to the recycling of Cl when the duct is secreting image.

References

Jiang Z, Grichtchenko II, Boron WF, Aronson PS. Specificity of anion exchange mediated by mouse Slc26a6. J Biol Chem. 2002;277:33963–33967.

Ko SB, Zeng W, Dorwart MR, et al. Gating of CFTR by the STAS domain of SLC26 transporters. Nat Cell Biol. 2004;6:343–350.

Mount DB, Romero MF. The SLC26 gene family of multifunctional anion exchangers. Pflugers Arch. 2004;447:710–721.

Secretin (via cAMP) and ACh (via Ca2+) stimulate image secretion by pancreatic ducts

When stimulated, the epithelial cells of the pancreatic duct secrete an isotonic NaHCO3 solution. The duct cells have receptors for secretin, ACh, GRP (all of which stimulate image secretion), and substance P (which inhibits it). CCK may also modulate ductular secretory processes.

Secretin is the most important humoral regulator of ductal image secretion. Activation of the secretin receptor on the duct cell stimulates adenylyl cyclase, which raises [cAMP]i. Because forskolin and cAMP analogs stimulate ductal image secretion, the secretin response has been attributed to its effect on [cAMP]i and activation of PKA. However, even low concentrations of secretin that do not measurably increase [cAMP]i can stimulate image secretion. This observation suggests that the secretin response may be mediated by (1) unmeasurably small increases in total cellular cAMP, (2) cAMP increases that are localized to small intracellular compartments, or (3) activation of alternative second-messenger pathways. Secretin acts by stimulating the apical CFTR Cl channel and the basolateral Na/HCO3 cotransporter without affecting the Na-H exchanger.

image secretion is also regulated by the parasympathetic division of the autonomic nervous system (see pp. 341–342). The postganglionic parasympathetic neurotransmitter ACh, acting through muscarinic receptors on the duct cell, increases [Ca2+]i and activates Ca2+-dependent protein kinases (PKC and the calmodulin-dependent protein kinases). The ACh effect is inhibited by atropine. Although ductular secretion in the rat is also stimulated by GRP, the second messenger mediating this effect is not known. In the duct cell, unlike in the acinar cell, GRP does not increase [Ca2+]i. GRP also does not raise [cAMP]i.

In the rat, both basal and stimulated ductular image secretion is inhibited by substance P. The second messenger mediating this effect is also unknown. Because substance P inhibits image secretion regardless of whether the secretagogue is secretin, ACh, or GRP—which apparently act via three different signal-transduction mechanisms—substance P probably acts at a site that is distal to the generation of second messengers, such as by inhibiting the Cl-HCO3 exchanger.

Apical membrane chloride channels are important sites of neurohumoral regulation

In the regulation of pancreatic duct cells by the neurohumoral mechanisms just discussed, the only effector proteins that have been identified as targets of the protein kinases and phosphatases are the apical Clchannels, basolateral K+ channels, and Na/HCO3 cotransporter. CFTR functions as a low-conductance apical Cl channel (see p. 120). CFTR has nucleotide-binding domains that control channel opening and closing as well as a regulatory domain with multiple potential PKA and PKC phosphorylation sites. Neurohumoral agents that control fluid and electrolyte secretion by the pancreatic duct cells act at this site. Agents that activate PKA are the most important regulators of CFTR function. PKC activation enhances the stimulatory effect of PKA on CFTR Cl transport, but alone it appears to have little direct effect on CFTR function. Thus, the CFTR Cl channel is regulated by ATP through two types of mechanisms: interaction with the nucleotide-binding domains and protein phosphorylation (see Fig. 5-10). imageN5-16

In addition to CFTR, pancreatic duct cells in some species have Ca2+-activated Cl channels (CaCCs) on the apical membrane. Not only does Ca2+ directly stimulate CaCCs, but cAMP may indirectly stimulate CaCCs by stimulating CFTR, which somehow promotes ATP efflux. Luminal ATP would then bind to an apical purinergic receptor, leading to the influx of Ca2+ and thus activation of CaCCs in an autocrine/paracrine fashion (see Fig. 43-6).

In rat pancreatic duct cells, Ca2+-sensitive basolateral K+ channels seem to be targets of neurohumoral stimulation. Activators of the cAMP pathway stimulate phosphorylation by PKA, thus enhancing the responsiveness of these channels to [Ca2+]i and increasing their probability of being open.

Pancreatic duct cells may also secrete glycoproteins

Although the primary function of the pancreatic duct cells is to secrete image and water, these cells may also synthesize and secrete various high-molecular-weight proteoglycans. Some of these proteins are structurally distinct from the mucin that is produced by the specialized goblet cells in the duct. Unlike the proteins that are secreted by acinar cells, the glycoproteins synthesized in duct cells are not accumulated in large secretion granules. Rather, they appear to be continuously synthesized and secreted from small cytoplasmic vesicles. Secretin increases the secretion of glycoproteins from these cells, but this action appears to result from stimulation of glycoprotein synthesis, rather than from stimulation of vesicular transport or exocytosis itself. The role of these proteins may be to protect against protease-mediated injury to mucosal cells.