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Novak et al.
Acid-base transport in pancreas the latter two, which are expressed in pancreas (see below), othercandidates remain to be explored.
Pancreatic ducts comprise 5–20% of the tissue mass, depend- ing on the species; morphologically they are different - progress-ing from flat centroacinar cells, cuboidal cells in intercalated, andsmall intralobular ducts to columnar heterogenous cells lininglarger distal ducts Bouwensand Pipeleers, ). At large, it is accepted that pancreatic ductssecrete isotonic NaHCO3 rich fluid. However, the concentrationof HCO− is not constant; it decreases with secretory rates—a pattern that is mirrored by Cl−. The HCO− excretory pat- terns are remarkably similar between various species, providingthat secretory rates are corrected for the duct mass In early studies it was proposedthat pancreatic secretion and ionic composition is a two stageprocess—primary secretion and ductal modification, the so calledadmixture hypothesis. Another, the exchange theory, also namedthe salvage mechanism, states that at lower secretory rates duc-tal transporters are presumably not saturated and therefore, are FIGURE 1 HCO− and H+ transport in gastric cells (A) and pancreatic
capable of exchanging luminal HCO− for interstitial Cl−. This duct cells (B). The models show schematically different types of epithelia
exchange phenomenon was first demonstrated on the main cat as single cells. The transport of H+ or HCO− to the bulk luminal fluid is duct . The third explanation, regarding vary- shown with large arrows. The small arrows on luminal side indicate HCO− ing HCO− concentrations, pertains H+ secretion from acini (see and H+ secretions to the mucosal buffer zone. Flux of HCO− and H+ to the above) or ducts (see below).
interstititum/blood side indicates expected alkaline or acid tides.
NOVEL ION CHANNELS AND PUMPS CONTRIBUTING TO
peptic and duodenal ulcers and reflux diseases ).
ACID-BASE TRANSPORT IN PANCREATIC DUCTS
In contrast, we do not understand the mechanism behind pan- The ion transport models for pancreatic ducts have been creatic alkaline (HCO−) secretion fully. Therefore, therapeutic described in several recent reviews Steward intervention is not possible, e.g., for cystic fibrosis patients.
and Ishiguro, ). The outline of the model is given in The PANCREATIC SECRETION—CONTRIBUTION FROM ACINI
following sections will focus on novel additions to the model.
AND DUCTS
Pancreas is composed of two main types of epithelia—secretory
PROTON PUMPS
acini and excretory ducts. Acini have relatively uniform mor- Ion channels and transporters proposed in the classical model phology. They secrete digestive enzymes, NaCl-rich fluid and for HCO− secretion rely on gradients created by the Na+/K+- various factors that contribute to signaling in down-stream ducts.
ATPase . However, we cannot explain formation of Studies on normal human and rodent pancreas, stimulated by high HCO− concentrations and the fact that inhibitors of NHE1, predominantly acinar agonists, e.g., cholecytokinin (CCK), result NBC (and NKCC1), and CA are relatively ineffective in blocking in neutral or weakly alkaline pancreatic juice However, a recent One solution is that a primary pump could be involved, such as study using acinar preparation and bioimaging techniques shows the vacuolar type H+-ATPase (V-H+-pump), to pump H+ out that acinar secretion is acidic due to acidic zymogen granules to interstitium and leave HCO− for the luminal transport. In (ZG) although acidity of mature ZG one study, such vacuolar H+ pump on the basolateral membrane has been discussed was proposed and detected immunohisto- ). Nevertheless, a potential acid load from acini challenging chemically Several functional studies gave proximal ducts has been considered ). One contradictory findings de possible defense mechanism could be activation of ducts by aci- Ondarza and Hootman, ). Taking an inspiration from gas- nar agonist; generally this seems not to be the case. Alternatively, tric glands, the colon and kidney distal tubules, we considered paracrine agonists such as ATP released by acini could stimulate whether pancreatic ducts express H+-K+-ATPases. Indeed, we ducts by purinergic signaling found that rodent ducts express both the gastric and non-gastric ). Lastly, pancreatic ducts might have ability to sense and (colonic) types H+-K+-ATPases Inhibition react to acid/base locally. There are a number of acid/base sen- of these with proton pump inhibitors reduced pHi recovery in sors at the single cell and whole organ level response to acid loads; more importantly, they reduced secretion in isolated pancreatic ducts. Thus, these functional studies sup- acid sensitive ASIC and TRP channels, HCO− sensitive adenylate port the theory that pancreatic ducts resemble gastric glands— cyclase, pH-sensitive K+ channels, and P2X receptors. Except for just working in reverse, expelling H+ toward the blood side

Novak et al.
Acid-base transport in pancreas FIGURE 2 Acid/base transport in pancreas. (A) The relation between
certain conditions, through Cl− channels. The luminal Cl− channels are CFTR secretory rates and HCO− concentrations in pancreatic juice of various and TMEM16A (see text). There are a number of K+ channels expressed on species. Secretions were stimulated by secretin and secretory rates were the luminal and basolateral membranes, e.g., KCa3.1, KCa1.1, KCNQ1 (see corrected for body weights. (B) The model of ion transport in a secreting
text). The luminal and basolateral H+-K+-ATPases are indicated in red and pancreatic duct cell with novel transporters, channels and luminal purinergic green, and supposedly contribute to the luminal buffer zone and the H+ efflux signaling and receptors indicated in color and discussed in the review.
to intersititum, respectively. Other ion channels and transporters, such as Intracellular HCO− is derived from CO NHE3, SLC26A3, NBC3, NKCC1, and aquaporins have a differential 2 through the action of carbonic anhydrase (CA) and from HCO− uptake via the electrogenic Na+–HCO− distribution in the duct tree and for simplicity are not included in the model.
cotransporter (pNBC, NBCe1). H+ is extruded at basolateral membrane by (C) Immunolocalization of the gastric (red) and non-gastric (green) H+-K+
the Na+/H+ exchanger (NHE1). HCO− efflux across the luminal membrane is pumps in rat pancreatic duct. The bar is 20 μm. Modified from mediated by the electrogenic Cl−/HCO− exchanger (SLC26A6), and under and leaving HCO− for the luminal transport The is—these luminal pumps are safeguarding luminal cell surface immunohistochemical study showed that the H+-K+-ATPases with acid secretions to protect against the bulk alkaline secre- (mainly colonic type) are localized to the basolateral membrane tions, which at pH >8 would be caustic to cells. Thus, pancreatic ducts would have protective buffer (and mucus) zone, which is However, H+-K+-ATPases, especially the gastric form, are reminiscent to the buffer zone in the stomach, though achieved also localized at or close to the luminal membrane by H+ rather than HCO− secretion In addition, ). It seems counterintuitive to place H+ pumps the luminal H+-K+ pumps would recirculate K+ extruded by the on the HCO− secreting luminal membrane. Nevertheless, there luminal K+ channels Lastly, luminal H+-K+ pumps are epithelia that are high HCO− secretors and yet express H+ in distal ducts would by virtue of H+ secretion have more impact pumps on the luminal membranes. For example, insect midgut on pancreatic juice composition at low flow rates and minor and marine fish intestine have functional V-H+-ATPase on the at high flow rates, thus, explaining excretory curves for HCO− luminal membranes Also other epithelia, which are not highHCO− secretors (HCO− <25 mM), express various H+ pumps Ca2+-ACTIVATED Cl− CHANNELS
on the luminal membranes. For example, airway epithelia trans- In addition to CFTR-dependent secretion, a number of studies port both base and acid, and the airway fluid layer is slightly showed that agonists acting via Ca2+-signaling stimulate Ca2+- acidic Some studies provide activated Cl− channels (CaCC) and thus, could support duct evidence for the presence of bafilomycin A sensitive V-H+ pump secretion Winpenny ); other studies show that transport is sensitive to SCH28080, The molecular identity of CaCC channels has been difficult to an inhibitor of gastric (and also non-gastric) H+-K+ pumps pinpoint [see After suggestions of CCl-2 and bestrophins, the TMEM16/ANO family was discovered (Caputo gastric, ouabain-sensitive H+-K+-pumps were also demonstrated et al., ), and especially in some studies Shan TMEM16A/ANO1 became a CaCC favorite. Recent studies show that human duct cell lines express TMEM16A, which re-localizes Coming back to the pancreatic luminal H+-K+ pumps, let from cytosol to the luminal membrane upon purinergic stimula- us speculate what their function may be. They could help to tion and gives rise to secretory potentials defend the cell against intracellular acidification, although there In human pancreatic samples immunohis- is a redundancy of acid/base transporters including several NHEs, tochemistry shows TMEM16A in centro-acinar and small ducts NBCs, and Cl−/HCO− exchangers Our proposal Novak et al.
Acid-base transport in pancreas It is relevant to ask whether TMEM16A and/or Ca2+ signal- ing pathways lead to HCO− secretion. There are a few studies in Pancreatic secretion regulated by hormonal and neural systems is support of this notion. For example, Ca2+ signaling via IRBIT stimulates NBCe1 A Paracrine regulation is less explored, but it is highly relevant as recent study on TMEM16A anion permeability shows that in it allows regulation within the gland and integration of acinar HEK293 cell expression system and mouse salivary acinar cells and ductal responses. Pancreatic ducts can be regulated by acinar the channel is directly modulated by calmodulin, which increases factors (trypsin, guanylin, ATP) as well as retrograde factors (bile its HCO− permeability This is supported by a study on ex vivo salivary glands stimulated with acetycholine, which induced production of HCO− rich pancreatic-like secre- centrate on purinergic signaling and present evidence that this tion when Cl− transport was inhibited signaling could fine-tune and coordinate pancreatic secretion on Nevertheless, it cannot be excluded that there are other molec- several fronts. Pancreatic ducts express several types of purinergic ular candidates for CaCC, or that CFTR can convey part of the receptors including members from the G-protein coupled recep- Ca2+-activated Cl− currents. The latter mechanism could involve tor families (adenosine, P2Y) and ligand-gated ion channels (P2X Ca2+ sensitive adenylate cyclases and tyrosine kinases (Src2/Pyk receptor) families that can potentially stimu- complex), both of which could alter activity of CFTR, as shown late a variety of intracellular signaling pathways for other epithelia Another effect at the CFTR level could be priming of some PKC ). These receptors regulate pancreatic isoforms that enhance CFTR activity [see duct ion transport, mucin secretion, and survival of fibrogenic )]. Lastly, it is highly unlikely that Ca2+ mediated signaling pancreatic stellate cells stands alone, rather the two major signaling pathways of Ca2+ and ATP originates from ZG where it is accumulated by the vesic- cAMP/PKA act synergistically in pancreatic ducts, e.g., via IRBIT ular nucleotide transporter VNUT regulation of CFTR and SLC26A6 ).
and in addition ATP is presumably released by nerves and ductalepithelium Burnstock K+ CHANNELS
and Novak, Various ecto-nucleotidases are expressed and The driving force for Cl− or HCO− exit is maintained by hyper- secreted, and potentially ATP/ADP and adenosine are effective polarizing membrane potential created by opening of K+ chan- regulators of ductal functions nels, and GK is both present on the basolateral and luminal ATP and UTP via P2 receptors have effects on intracellular analysis has shown that stimulation of luminal K+ channels con- Ca2+, intracellular pH, and transepithelial transport in both iso- tributes with at least with 10% to the total conductance. Modeling lated ducts and in vivo pancreas in salivary glands confirms that such ratio of luminal to basolat- ). The physiological response to nucleotides is side specific.
eral K+ channels would optimize secretion without destroying the Basolateral UTP inhibits secretion, most likely due to inhibi- transepithelial potential and transport tion of KCa1.1 channels, presumably to prevent overextension Furthermore, luminal K+ channels could of ducts. In contrast, luminal UTP/ATP application causes duct contribute to secreted K+, as pancreatic juice contains 4–8 mM secretion and activation and Cl− and K+ channels ). In particular KCa3.1 ). The molecular identity of some K+ channels in pancre- channel activation potentiates secretion (see above). It is well doc- atic ducts is known, however, the exact localization and function umented that purinergic receptor stimulation activates CFTR, remains to be verified [see )]. The Cl−/HCO− exchangers and TMEM16A on the luminal mem- KCa1.1 channels (maxi-K, BK, coded by KCNMA1) are present brane Furthermore, in pancreatic ducts ).
P2 receptors activate CaCC and CFTR interdependently and syn- The latter study proposes that these channels are expressed on the ergistically, though exact receptors and signaling pathways remain luminal membrane and activated by low concentrations of bile to be elucidated (see above). In addition, some effects can be due acids. However, earlier patch-clamp studies indicated that these to stimulation of A2A and A2B receptors, which stimulate CFTR channels were also located basolaterally Hede et al., The KCa3.1 channel (IK, SK4, coded by KCNN4) A number of processes in purinergic signaling are pH sen- was demonstrated in pancreatic ducts Jung sitive, and this must be of relevance in pancreatic duct lumen.
et al., Immunolocalization indicates For example, nucleotidase activities, CD39 and CD73 types, are that KCa3.1 is expressed on both membranes, though stronger on stimulated at alkaline pH 8–9 the luminal one Interestingly, the channel activator ), thus, favoring conversion of ATP to adenosine in duct EBIO enhanced secretion potentials Wang lumen. Furthermore, purinergic receptors are also pH sensitive.
et al., ). Recent studies on pancreatic ducts offers molecu- From other preparations we know that extracellular acidifica- lar identities of several K+ channels, including KVLQT1, HERG, tion enhanced the potency of UTP up to 10 fold on the rat EAG2; Slick, and Slack and interestingly the P2Y4 but not P2Y2 receptors ), and the pH sensor TASK-2 However, the function and P2X2 receptors was activated by acid pH regulation of these channels in pancreas physiology needs to be Extracellular alkalinization enhances activity the P2X4 and P2X7 receptors Several types Novak et al.
Acid-base transport in pancreas of these receptors are expressed in duct lumen including the Bilbao, P. S., Katz, S., and Boland, R. (2012). Interaction of purinergic recep- P2Y2 and P2X7 receptors, and these enhance pancreatic secretion tors with GPCRs, ion channels, tyrosine kinase and steroid hormone receptors and integrate acini-to-duct signaling orchestrates cell function. Purinergic Signal. 8, 91–103. doi: 10.1007/s11302-011-9260-9 Billet, A., and Hanrahan, J. W. (2013). The secret life of CFTR as a calcium-activated chloride channel. J. Physiol. 591, 5273–5278. doi: 10.1113/jphysiol.2013.261909 SUMMARY AND PERSPECTIVES
Billet, A., Luo, Y., Balghi, H., and Hanrahan, J. W. (2013). Role of tyrosine phos- The original cellular model for pancreatic HCO− secretion has phorylation in the muscarinic activation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). J. Biol. Chem. 288, 21815–21823. doi: been supplemented with molecular identities for many ion trans- porters/channels. The present review challenges present concepts Bodin, P., and Burnstock, G. (2001). Purinergic signaling: ATP release. Neurochem. by including active H+ pumps in the model, and by compar- Res. 26, 959–969. doi: 10.1023/A:1012388618693 ing basic processes in pancreas and stomach. Furthermore, we Bouwens, L., and Pipeleers, D. G. (1998). Extra-insular beta cells associated with present new additions to the model—Ca2+-activated Cl− and K+ ductules are frequent in adult human pancreas. Diabetologia 41, 629–633. doi:10.1007/s001250050960 channels, and propose that they work in synergy to regulate secre- Bro-Rasmussen, F., Killmann, S. A., and Thaysen, J. H. (1956). The composition tion. On the organ level, acini, and ducts integrate their function of pancreatic juice as compared to sweat, parotid saliva and tears. Acta Physiol. in acid/base transport and regulation, the latter exemplified by Scand. 37, 97–113. doi: 10.1111/j.1748-1716.1956.tb01346.x purinergic signaling. Further challenges lay in understanding dys- Brown, D., and Wagner, C. A. (2012). Molecular mechanisms of acid-base sensing by the kidney. J. Am. Soc. Nephrol. 23, 774–780. doi: 10.1681/ASN.2012010029 regulation of acid-base transport in pancreas pathophysiology. In Burnstock, G. (2007). Purine and pyrimidine receptors. Cell Mol. Life Sci. 64, CF patients and animal models, pancreatic juice pH decreases 1471–1483. doi: 10.1007/s00018-007-6497-0 from values >8.1 to <6.6, and pancreas contributes to duode- Burnstock, G., and Novak, I. (2012). Purinergic signaling in the pancreas in health nal hyperacidity [see and disease. J. Endocrinol. 213, 123–141. doi: 10.1530/JOE-11-0434 It is not clear whether the prob- Caflisch, C. R., Solomon, S., and Galey, W. R. (1979). Exocrine ductal pCO2 in the rabbit pancreas. Pflugers Arch. 380, 121–125. doi: 10.1007/BF00582146 lem relates to ductal and/or acinar secretion. In acute pancreatitis, Caputo, A., Caci, E., Ferrera, L., Pedemonte, N., Barsanti, C., Sondo, E., which has complex etiologies, it is now appreciated that defec- et al. (2008). TMEM16A, a membrane protein associated with calcium- tive pancreatic duct secretion can be the initiating factor (Lee dependent chloride channel activity. Science 322, 590–594. doi: 10.1126/science.
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Surprenant, A., and North, R. A. (2009). Signaling at purinergic P2X recep- ducted in the absence of any commercial or financial relationships that could be tors. Annu. Rev. Physiol. 71, 333–359. doi: 10.1146/annurev.physiol.70.113006.
construed as a potential conflict of interest.
Szalmay, G., Varga, G., Kajiyama, F., Yang, X. S., Lang, T. F., Case, R. M., et al.
Received: 07 October 2013; paper pending published: 23 October 2013; accepted: 04 (2001). Bicarbonate and fluid secretion evoked by cholecystokinin, bombesin December 2013; published online: 20 December 2013. and acetylcholine in isolated guinea-pig pancreatic ducts. J. Physiol. (Lond.) 535, Citation: Novak I, Haanes KA and Wang J (2013) Acid-base transport in pancreas— 795–807. doi: 10.1111/j.1469-7793.2001.00795.x new challenges. Front. Physiol. 4:380. doi:
Tresguerres, M., Buck, J., and Levin, L. R. (2010). Physiological carbon dioxide, This article was submitted to Membrane Physiology and Membrane Biophysics, a bicarbonate, and pH sensing. Pflugers Arch. 460, 953–964. doi: 10.1007/s00424- section of the journal Frontiers in Physiology. Copyright 2013 Novak, Haanes and Wang. This is an open-access article dis- Uc, A., Stoltz, D. A., Ludwig, P., Pezzulo, A., Griffin, M., bu-El-Haija, M., et al.
tributed under the terms of the The (2011). Pancreatic and biliary secretion differ in cystic fibrosis and wild-type use, distribution or reproduction in other forums is permitted, provided the original pigs. J. Cystic Fibrosis 10, S69. doi: 10.1016/S1569-1993(11)60285-3 author(s) or licensor are credited and that the original publication in this jour- Venglovecz, V., Hegyi, P., Rakonczay, Z. Jr., Tiszlavicz, L., Nardi, A., Grunnet, nal is cited, in accordance with accepted academic practice. No use, distribution or M., et al. (2011). Pathophysiological relevance of apical large-conductance reproduction is permitted which does not comply with these terms.

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