The Exocrine Pancreas: The Acinar-Ductal Tango in Physiology and Pathophysiology

  • Peter HegyiEmail author
  • Ole H. Petersen
Part of the Reviews of Physiology, Biochemistry and Pharmacology book series (REVIEWS, volume 165)


There are many reviews of pancreatic acinar cell function and also of pancreatic duct function, but there is an almost total absence of synthetic reviews bringing the integrated functions of these two vitally and mutually interdependent cells together. This is what we have attempted to do in this chapter. In the first part, we review the normal integrated function of the acinar-ductal system, with particular emphasis on how regulation of one type of cell also influences the other cell type. In the second part, we review a range of pathological processes, particularly those involved in acute pancreatitis (AP), an often-fatal human disease in which the pancreas digests itself, in order to explore how malfunction of one of the cell types adversely affects the function of the other.


Bile Acid Chronic Pancreatitis Pancreatic Duct Acinar Cell Acute Pancreatitis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.





Acid-sensing ion channels


Acute pancreatitis




Alpha-d-glucose-1-phosphate uridylyltransferase


Ca2+-activated Cl channels




Cationic trypsinogen




Chymotrypsin C


Cyclic adenosine monophosphate


Cyclic guanosine monophosphate


Cystic fibrosis


Diisothiocyanostilbene disulfonate


Fatty acid ethyl esters


Fatty acids


Inositol triphosphate


Intracellular Ca2+ level


Inwardly rectifying K+ -8


Ionotropic purinoceptor


Na+/H+ exchangers


Pancreatic secretory trypsin inhibitor


Plasma membrane Ca2+ ATPase pump


Potassium voltage-gated channel subfamily Q, member 1


Protease-activated receptor 2


Reactive oxygen species


Sarco/endoplasmic reticulum Ca2+-ATPase


Taurolithocholic acid


Transient receptor potential ion channels of the vanilloid subtype


Two-pore domain potassium channels


Two-pore domain weakly inward rectifying


Zymogen granules



The research on pancreatic ducts was mostly supported by Hungarian National Development Agency grants (TÁMOP-4.2.2.A-11/1/KONV-2012-0035, TÁMOP-4.2.2-A-11/1/KONV-2012-0052 TÁMOP-4.2.2.A-11/1/KONV-2012-0073), the Hungarian Scientific Research Fund (OTKA NF105758, NF100677), and the Hungarian Academy of Sciences (BO 00174/10/5). Whereas, the experimental work on acinar cells was supported by Medical Research Council Programme Grants G0700167 and MR/J002771/1 as well as a Medical Research Council Professorship for OHP (G19/22/2). The authors declare that the experiments performed by them using the above-mentioned sources comply with the current laws of the country in which they were performed.


  1. Alexandre M, Pandol SJ, Gorelick FS, Thrower EC (2011) The emerging role of smoking in the development of pancreatitis. Pancreatology 11:469–474PubMedGoogle Scholar
  2. Allen-Mersh TG (1985) What is the significance of pancreatic ductal mucinous hyperplasia? Gut 26:825–833PubMedGoogle Scholar
  3. Aponte GW, Park K, Hess R, Garcia R, Taylor IL (1989) Meal-induced peptide tyrosine tyrosine inhibition of pancreatic secretion in the rat. FASEB J 3:1949–1955PubMedGoogle Scholar
  4. Apte MV, Norton ID, Wilson JS (1994) Ethanol induced acinar cell injury. Alcohol Alcohol Suppl 2:365–368PubMedGoogle Scholar
  5. Apte MV, Wilson JS, McCaughan GW, Korsten MA, Haber PS, Norton ID, Pirola RC (1995) Ethanol-induced alterations in messenger RNA levels correlate with glandular content of pancreatic enzymes. J Lab Clin Med 125:634–640PubMedGoogle Scholar
  6. Apte MV, Pirola RC, Wilson JS (2010) Mechanisms of alcoholic pancreatitis. J Gastroenterol Hepatol 25:1816–1826PubMedGoogle Scholar
  7. Argent BE (2006) Cell physiology of pancreatic ducts. In: Johnson LR (ed) Physiology of the gastrointestinal tract, vol 2. Elsevier, San Diego, pp 1376–1396Google Scholar
  8. Armstrong CP, Taylor TV, Torrance HB (1985) Effects of bile, infection and pressure on pancreatic duct integrity. Br J Surg 72:792–795PubMedGoogle Scholar
  9. Awla D, Abdulla A, Regner S, Thorlacius H (2011) TLR4 but not TLR2 regulates inflammation and tissue damage in acute pancreatitis induced by retrograde infusion of taurocholate. Inflamm Res 60:1093–1098PubMedGoogle Scholar
  10. Barrow SL, Voronina SG, da Silva Xavier G, Chvanov MA, Longbottom RE, Gerasimenko OV, Petersen OH, Rutter GA, Tepikin AV (2008) ATP depletion inhibits Ca2+ release, influx and extrusion in pancreatic acinar cells but not pathological Ca2+ responses induced by bile. Pflugers Arch 455:1025–1039PubMedGoogle Scholar
  11. Behrendorff N, Floetenmeyer M, Schwiening C, Thorn P (2010). Protons released during pancreatic acinar cell secretion acidify the lumen and contribute to pancreatitis in mice. Gastroenterology 139:1711–1720, 1720 e1711–1715Google Scholar
  12. Bhoomagoud M, Jung T, Atladottir J, Kolodecik TR, Shugrue C, Chaudhuri A, Thrower EC, Gorelick FS (2009) Reducing extracellular pH sensitizes the acinar cell to secretagogue-induced pancreatitis responses in rats. Gastroenterology 137:1083–1092PubMedGoogle Scholar
  13. Booth DM, Murphy JA, Mukherjee R, Awais M, Neoptolemos JP, Gerasimenko OV, Tepikin AV, Petersen OH, Sutton R, Criddle DN (2011) Reactive oxygen species induced by bile acid induce apoptosis and protect against necrosis in pancreatic acinar cells. Gastroenterology 140:2116–2125PubMedGoogle Scholar
  14. Braganza JM, Rao JJ (1978) Disproportionate reduction in tryptic response to endogenous compared with exogenous stimulation in chronic pancreatitis. Br Med J 2:392–394PubMedGoogle Scholar
  15. Braun M, Thevenod F (2000) Photoaffinity labeling and purification of ZG-16p, a high-affinity dihydropyridine binding protein of rat pancreatic zymogen granule membranes that regulates a K(+)-selective conductance. Mol Pharmacol 57:308–316PubMedGoogle Scholar
  16. Bruce JI, Yang X, Ferguson CJ, Elliott AC, Steward MC, Case RM, Riccardi D (1999) Molecular and functional identification of a Ca2+ (polyvalent cation)-sensing receptor in rat pancreas. J Biol Chem 274:20561–20568PubMedGoogle Scholar
  17. Chen X, Andrews PC (2008) Purification and proteomics analysis of pancreatic zymogen granule membranes. Methods Mol Biol 432:275–287PubMedGoogle Scholar
  18. Chen X, Andrews PC (2009) Quantitative proteomics analysis of pancreatic zymogen granule membrane proteins. Methods Mol Biol 528:327–338PubMedGoogle Scholar
  19. Chen EY, Yang N, Quinton PM, Chin WC (2010) A new role for bicarbonate in mucus formation. Am J Physiol Lung Cell Mol Physiol 299:L542–L549PubMedGoogle Scholar
  20. Cosen-Binker LI, Lam PP, Binker MG, Reeve J, Pandol S, Gaisano HY (2007) Alcohol/cholecystokinin-evoked pancreatic acinar basolateral exocytosis is mediated by protein kinase C alpha phosphorylation of Munc18c. J Biol Chem 282:13047–13058PubMedGoogle Scholar
  21. Cosen-Binker LI, Binker MG, Wang CC, Hong W, Gaisano HY (2008) VAMP8 is the v-SNARE that mediates basolateral exocytosis in a mouse model of alcoholic pancreatitis. J Clin Invest 118:2535–2551PubMedGoogle Scholar
  22. Criddle DN, Raraty MG, Neoptolemos JP, Tepikin AV, Petersen OH, Sutton R (2004) Ethanol toxicity in pancreatic acinar cells: mediation by nonoxidative fatty acid metabolites. Proc Natl Acad Sci USA 101:10738–10743PubMedGoogle Scholar
  23. Criddle DN, Murphy J, Fistetto G, Barrow S, Tepikin AV, Neoptolemos JP, Sutton R, Petersen OH (2006) Fatty acid ethyl esters cause pancreatic calcium toxicity via inositol trisphosphate receptors and loss of ATP synthesis. Gastroenterology 130:781–793PubMedGoogle Scholar
  24. Doege H, Stahl A (2006) Protein-mediated fatty acid uptake: novel insights from in vivo models. Physiology (Bethesda) 21:259–268Google Scholar
  25. Dolai S, Liang T, Lam PP, Fernandez NA, Chidambaram S, Gaisano HY (2012) Effects of ethanol metabolites on exocytosis of pancreatic acinar cells in rats. Gastroenterology 143(832–843):e831–e837Google Scholar
  26. Farmer RC, Tweedie J, Maslin S, Reber HA, Adler G, Kern H (1984) Effects of bile salts on permeability and morphology of main pancreatic duct in cats. Dig Dis Sci 29:740–751PubMedGoogle Scholar
  27. Ferdek PE, Gerasimenko JV, Peng S, Tepikin AV, Petersen OH, Gerasimenko OV (2012) A novel role for Bcl-2 in regulation of cellular calcium extrusion. Curr Biol 22:1241–1246PubMedGoogle Scholar
  28. Findlay I, Petersen OH (1983) The extent of dye-coupling between exocrine acinar cells of the mouse pancreas. The dye-coupled acinar unit. Cell Tissue Res 232:121–127PubMedGoogle Scholar
  29. Freedman SD (1998) New concepts in understanding the pathophysiology of chronic pancreatitis. Int J Pancreatol 24:1–8PubMedGoogle Scholar
  30. Freedman SD, Kern HF, Scheele GA (1994) Apical membrane trafficking during regulated pancreatic exocrine secretion – role of alkaline pH in the acinar lumen and enzymatic cleavage of GP2, a GPI-linked protein. Eur J Cell Biol 65:354–365PubMedGoogle Scholar
  31. Freedman SD, Kern HF, Scheele GA (1998a) Acinar lumen pH regulates endocytosis, but not exocytosis, at the apical plasma membrane of pancreatic acinar cells. Eur J Cell Biol 75:153–162PubMedGoogle Scholar
  32. Freedman SD, Kern HF, Scheele GA (1998b) Cleavage of GPI-anchored proteins from the plasma membrane activates apical endocytosis in pancreatic acinar cells. Eur J Cell Biol 75:163–173PubMedGoogle Scholar
  33. Freedman SD, Kern HF, Scheele GA (2001) Pancreatic acinar cell dysfunction in CFTR(−/−) mice is associated with impairments in luminal pH and endocytosis. Gastroenterology 121:950–957PubMedGoogle Scholar
  34. Gasser KW, DiDomenico J, Hopfer U (1988) Secretagogues activate chloride transport pathways in pancreatic zymogen granules. Am J Physiol 254:G93–G99PubMedGoogle Scholar
  35. Gerasimenko JV, Flowerdew SE, Voronina SG, Sukhomlin TK, Tepikin AV, Petersen OH, Gerasimenko OV (2006) Bile acids induce Ca2+ release from both the endoplasmic reticulum and acidic intracellular calcium stores through activation of inositol trisphosphate receptors and ryanodine receptors. J Biol Chem 281:40154–40163PubMedGoogle Scholar
  36. Gerasimenko JV, Lur G, Sherwood MW, Ebisui E, Tepikin AV, Mikoshiba K, Gerasimenko OV, Petersen OH (2009) Pancreatic protease activation by alcohol metabolite depends on Ca2+ release via acid store IP3 receptors. Proc Natl Acad Sci USA 106:10758–10763PubMedGoogle Scholar
  37. Gerasimenko JV, Lur G, Ferdek P, Sherwood MW, Ebisui E, Tepikin AV, Mikoshiba K, Petersen OH, Gerasimenko OV (2011) Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca2+ release through IP3 receptors. Proc Natl Acad Sci USA 108:5873–5878PubMedGoogle Scholar
  38. Goebell H, Baltzer G, Schlott KA, Bode C (1973) Parallel secretion of calcium and enzymes by the human pancreas. Digestion 8:336–346PubMedGoogle Scholar
  39. Gorelick FS (2003) Alcohol and zymogen activation in the pancreatic acinar cell. Pancreas 27:305–310PubMedGoogle Scholar
  40. Gullo L, Priori P, Costa PL, Mattioli G, Labo G (1984) Action of secretin on pancreatic enzyme secretion in man. Studies on pure pancreatic juice. Gut 25:867–873PubMedGoogle Scholar
  41. Haanes KA, Novak I (2010) ATP storage and uptake by isolated pancreatic zymogen granules. Biochem J 429:303–311PubMedGoogle Scholar
  42. Haber PS, Wilson JS, Apte MV, Pirola RC (1993) Fatty acid ethyl esters increase rat pancreatic lysosomal fragility. J Lab Clin Med 121:759–764PubMedGoogle Scholar
  43. Haber PS, Wilson JS, Apte MV, Korsten MA, Pirola RC (1994) Chronic ethanol consumption increases the fragility of rat pancreatic zymogen granules. Gut 35:1474–1478PubMedGoogle Scholar
  44. Hegyi P, Rakonczay Z Jr (2007) The inhibitory pathways of pancreatic ductal bicarbonate secretion. Int J Biochem Cell Biol 39:25–30PubMedGoogle Scholar
  45. Hegyi P, Rakonczay Z (2010) Insufficiency of electrolyte and fluid secretion by pancreatic ductal cells leads to increased patient risk for pancreatitis. Am J Gastroenterol 105:2119–2120PubMedGoogle Scholar
  46. Hegyi P, Gray MA, Argent BE (2003) Substance P inhibits bicarbonate secretion from guinea pig pancreatic ducts by modulating an anion exchanger. Am J Physiol Cell Physiol 285:C268–C276PubMedGoogle Scholar
  47. Hegyi P, Ordog B, Rakonczai Z Jr, Takacs T, Lonovics J, Szabolcs A, Sari R, Toth A, Papp JG, Varro A, Kovacs MK, Gray MA, Argent BE, Boldogkoi Z (2005a) Effect of herpesvirus infection on pancreatic duct cell secretion. World J Gastroenterol 11:5997–6002PubMedGoogle Scholar
  48. Hegyi P, Rakonczay Z Jr, Tiszlavicz L, Varro A, Toth A, Racz G, Varga G, Gray MA, Argent BE (2005b) Protein kinase C mediates the inhibitory effect of substance P on HCO3 secretion from guinea pig pancreatic ducts. Am J Physiol Cell Physiol 288:C1030–C1041PubMedGoogle Scholar
  49. Hegyi P, Maleth J, Venglovecz V, Rakonczay Z Jr (2011a) Pancreatic ductal bicarbonate secretion: challenge of the acinar acid load. Front Physiol 2:36PubMedGoogle Scholar
  50. Hegyi P, Pandol S, Venglovecz V, Rakonczay Z Jr (2011b) The acinar-ductal tango in the pathogenesis of acute pancreatitis. Gut 60:544–552PubMedGoogle Scholar
  51. Hegyi P, Rakonczay Z, Venglovecz V, Wittmann T, Maleth J (2012) Non-oxidative ethanol metabolites induce intracellular ATP depletion and inhibit pancreatic ductal bicarbonate secretion in human pancreatic ductal epithelial cell line. Gastroenterology 142:S460–S460Google Scholar
  52. Henriksen KL, Novak I (2003) Effect of ATP on intracellular pH in pancreatic ducts involves P2X7 receptors. Cell Physiol Biochem 13:93–102PubMedGoogle Scholar
  53. Hirota M, Shimosegawa T, Masamune A, Kikuta K, Kume K, Hamada S, Kihara Y, Satoh A, Kimura K, Tsuji I, Kuriyama S (2012) The sixth nationwide epidemiological survey of chronic pancreatitis in Japan. Pancreatology 12:79–84PubMedGoogle Scholar
  54. Holzer P (2003) Acid-sensitive ion channels in gastrointestinal function. Curr Opin Pharmacol 3:618–625PubMedGoogle Scholar
  55. Holzer P (2007) Taste receptors in the gastrointestinal tract. V. Acid sensing in the gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol 292:G699–G705PubMedGoogle Scholar
  56. Ignath I, Hegyi P, Venglovecz V, Szekely CA, Carr G, Hasegawa M, Inoue M, Takacs T, Argent BE, Gray MA, Rakonczay Z Jr (2009) CFTR expression but not Cl transport is involved in the stimulatory effect of bile acids on apical Cl/HCO3 exchange activity in human pancreatic duct cells. Pancreas 38:921–929PubMedGoogle Scholar
  57. Ishiguro H, Naruse S, Kitagawa M, Hayakawa T, Case RM, Steward MC (1999) Luminal ATP stimulates fluid and HCO3 secretion in guinea-pig pancreatic duct. J Physiol 519(Pt 2):551–558PubMedGoogle Scholar
  58. Iwatsuki N, Petersen OH (1978) Electrical coupling and uncoupling of exocrine acinar cells. J Cell Biol 79:533–545PubMedGoogle Scholar
  59. Iwatsuki N, Petersen OH (1979) Direct visualization of cell to cell coupling: transfer of fluorescent probes in living mammalian pancreatic acini. Pflugers Arch 380:277–281PubMedGoogle Scholar
  60. Iwatsuki N, Petersen OH (1981) Dissociation between stimulant-evoked acinar membrane resistance change and amylase secretion in the mouse parotid gland. J Physiol 314:79–84PubMedGoogle Scholar
  61. Kazal LA, Spicer DS, Brahinsky RA (1948) Isolation of a crystalline trypsin inhibitor-anticoagulant protein from pancreas. J Am Chem Soc 70:3034–3040PubMedGoogle Scholar
  62. Keller PJ, Allan BJ (1967) The protein composition of human pancreatic juice. J Biol Chem 242:281–287PubMedGoogle Scholar
  63. Kelly ML, Abu-Hamdah R, Jeremic A, Cho SJ, Ilie AE, Jena BP (2005) Patch clamped single pancreatic zymogen granules: direct measurements of ion channel activities at the granule membrane. Pancreatology 5:443–449PubMedGoogle Scholar
  64. Kemeny LV, Hegyi P, Rakonczay Z Jr, Borka K, Korompay A, Gray MA, Argent BE, Venglovecz V (2011) Substance P inhibits pancreatic ductal bicarbonate secretion via neurokinin receptors 2 and 3 in the guinea pig exocrine pancreas. Pancreas 40:793–795PubMedGoogle Scholar
  65. Kim JY, Kim KH, Lee JA, Namkung W, Sun AQ, Ananthanarayanan M, Suchy FJ, Shin DM, Muallem S, Lee MG (2002) Transporter-mediated bile acid uptake causes Ca2+−dependent cell death in rat pancreatic acinar cells. Gastroenterology 122:1941–1953PubMedGoogle Scholar
  66. Ko SB, Mizuno N, Yatabe Y, Yoshikawa T, Ishiguro H, Yamamoto A, Azuma S, Naruse S, Yamao K, Muallem S, Goto H (2010) Corticosteroids correct aberrant CFTR localization in the duct and regenerate acinar cells in autoimmune pancreatitis. Gastroenterology 138:1988–1996PubMedGoogle Scholar
  67. Ko SB, Azuma S, Yoshikawa T, Yamamoto A, Kyokane K, Ko MS, Ishiguro H (2012) Molecular mechanisms of pancreatic stone formation in chronic pancreatitis. Front Physiol 3:415PubMedGoogle Scholar
  68. Kordas KS, Sperlagh B, Tihanyi T, Topa L, Steward MC, Varga G, Kittel A (2004) ATP and ATPase secretion by exocrine pancreas in rat, guinea pig, and human. Pancreas 29:53–60PubMedGoogle Scholar
  69. Kubisch CH, Logsdon CD (2008) Endoplasmic reticulum stress and the pancreatic acinar cell. Expert Rev Gastroenterol Hepatol 2:249–260PubMedGoogle Scholar
  70. Kulaksiz H, Cetin Y (2001) Uroguanylin and guanylate cyclase C in the human pancreas: expression and mutuality of ligand/receptor localization as indicators of intercellular paracrine signaling pathways. J Endocrinol 170:267–275PubMedGoogle Scholar
  71. Kulaksiz H, Schmid A, Honscheid M, Eissele R, Klempnauer J, Cetin Y (2001) Guanylin in the human pancreas: a novel luminocrine regulatory pathway of electrolyte secretion via cGMP and CFTR in the ductal system. Histochem Cell Biol 115:131–145PubMedGoogle Scholar
  72. Lam KY, Leung PS (2002) Regulation and expression of a renin-angiotensin system in human pancreas and pancreatic endocrine tumours. Eur J Endocrinol 146:567–572PubMedGoogle Scholar
  73. Lam PP, Cosen Binker LI, Lugea A, Pandol SJ, Gaisano HY (2007) Alcohol redirects CCK-mediated apical exocytosis to the acinar basolateral membrane in alcoholic pancreatitis. Traffic 8:605–617PubMedGoogle Scholar
  74. Laposata EA, Lange LG (1986) Presence of nonoxidative ethanol metabolism in human organs commonly damaged by ethanol abuse. Science 231:497–499PubMedGoogle Scholar
  75. Lee M, Muallem S (2008) Physiology of duct cell secretion. In: HB (ed) The pancreas. Blackwell, Massachusetts, pp 78–91Google Scholar
  76. Lee MG, Ahn W, Choi JY, Luo X, Seo JT, Schultheis PJ, Shull GE, Kim KH, Muallem S (2000) Na(+)-dependent transporters mediate HCO(3)(−) salvage across the luminal membrane of the main pancreatic duct. J Clin Invest 105:1651–1658PubMedGoogle Scholar
  77. Lee WK, Torchalski B, Roussa E, Thevenod F (2008) Evidence for KCNQ1 K+ channel expression in rat zymogen granule membranes and involvement in cholecystokinin-induced pancreatic acinar secretion. Am J Physiol Cell Physiol 294:C879–C892PubMedGoogle Scholar
  78. Leung PS (2007) The physiology of a local renin-angiotensin system in the pancreas. J Physiol 580:31–37PubMedGoogle Scholar
  79. Leung PS, Chan HC, Fu LX, Wong PY (1997) Localization of angiotensin II receptor subtypes AT1 and AT2 in the pancreas of rodents. J Endocrinol 153:269–274PubMedGoogle Scholar
  80. Leung PS, Chan WP, Wong TP, Sernia C (1999) Expression and localization of the renin-angiotensin system in the rat pancreas. J Endocrinol 160:13–19PubMedGoogle Scholar
  81. Li Z, Lu M, Chu J, Qiao X, Meng X, Sun B, Zhang W, Xue D (2012) Early proteome analysis of rat pancreatic acinar AR42J cells treated with taurolithocholic acid 3-sulfate. Pancreatology 12:248–256PubMedGoogle Scholar
  82. Liddle RA (2007) The role of transient receptor potential vanilloid 1 (TRPV1) channels in pancreatitis. Biochim Biophys Acta 1772:869–878PubMedGoogle Scholar
  83. Lugea A, Tischler D, Nguyen J, Gong J, Gukovsky I, French SW, Gorelick FS, Pandol SJ (2010) Adaptive unfolded protein response attenuates alcohol-induced pancreatic damage. Gastroenterology 140:987–997PubMedGoogle Scholar
  84. Luo X, Zheng W, Yan M, Lee MG, Muallem S (1999) Multiple functional P2X and P2Y receptors in the luminal and basolateral membranes of pancreatic duct cells. Am J Physiol 277:C205–C215PubMedGoogle Scholar
  85. Luo X, Choi JY, Ko SB, Pushkin A, Kurtz I, Ahn W, Lee MG, Muallem S (2001) HCO3 salvage mechanisms in the submandibular gland acinar and duct cells. J Biol Chem 276:9808–9816PubMedGoogle Scholar
  86. Lur G, Haynes LP, Prior IA, Gerasimenko OV, Feske S, Petersen OH, Burgoyne RD, Tepikin AV (2009) Ribosome-free terminals of rough ER allow formation of STIM1 puncta and segregation of STIM1 from IP(3) receptors. Curr Biol 19:1648–1653PubMedGoogle Scholar
  87. Maleth J, Venglovecz V, Razga Z, Tiszlavicz L, Rakonczay Z Jr, Hegyi P (2011) Non-conjugated chenodeoxycholate induces severe mitochondrial damage and inhibits bicarbonate transport in pancreatic duct cells. Gut 60:136–138PubMedGoogle Scholar
  88. Maleth J, Rakonczay Z Jr, Venglovecz V, Dolman NJ, Hegyi P (2013) Central role of mitochondrial injury in the pathogenesis of acute pancreatitis. Acta Physiol (Oxf) 207(2):226–235Google Scholar
  89. Marteau C, Silviani V, Ducroc R, Crotte C, Gerolami A (1995) Evidence for apical Na+/H+ exchanger in bovine main pancreatic duct. Dig Dis Sci 40:2336–2340PubMedGoogle Scholar
  90. Meda P, Findlay I, Kolod E, Orci L, Petersen OH (1983) Short and reversible uncoupling evokes little change in the gap junctions of pancreatic acinar cells. J Ultrastruct Res 83:69–84PubMedGoogle Scholar
  91. Muili KA, Wang D, Orabi AI, Sarwar S, Luo Y, Javed TA, Eisses JF, Mahmood SM, Jin S, Singh VP, Ananthanaravanan M, Perides G, Williams JA, Molkentin JD, Husain SZ (2013) Bile acids induce pancreatic acinar cell injury and pancreatitis by activating calcineurin. J Biol Chem 288(1):570–580Google Scholar
  92. Mukherjee R, Criddle DN, Gukovskaya A, Pandol S, Petersen OH, Sutton R (2008) Mitochondrial injury in pancreatitis. Cell Calcium 44:14–23PubMedGoogle Scholar
  93. Murphy JA, Criddle DN, Sherwood M, Chvanov M, Mukherjee R, McLaughlin E, Booth D, Gerasimenko JV, Raraty MG, Ghaneh P, Neoptolemos JP, Gerasimenko OV, Tepikin AV, Green GM, Reeve JR Jr, Petersen OH, Sutton R (2008) Direct activation of cytosolic Ca2+ signaling and enzyme secretion by cholecystokinin in human pancreatic acinar cells. Gastroenterology 135:632–641PubMedGoogle Scholar
  94. Noble MD, Romac J, Vigna SR, Liddle RA (2008) A pH-sensitive, neurogenic pathway mediates disease severity in a model of post-ERCP pancreatitis. Gut 57:1566–1571PubMedGoogle Scholar
  95. Novak I (2008) Purinergic receptors in the endocrine and exocrine pancreas. Purinergic Signal 4:237–253PubMedGoogle Scholar
  96. Opie EL (1901) The etiology of acute hemorrhagic pancreatitis. Johns Hopkins Hosp Bull 12:182–188Google Scholar
  97. Owyang C, MJ D (2009) Chronic pancreatitis. In: Yamada T (ed) Textbook of gastroenterology, vol 2. Wiley-Blackwell, Oxford, pp 1811–1853Google Scholar
  98. Page AJ, Brierley SM, Martin CM, Price MP, Symonds E, Butler R, Wemmie JA, Blackshaw LA (2005) Different contributions of ASIC channels 1a, 2, and 3 in gastrointestinal mechanosensory function. Gut 54:1408–1415PubMedGoogle Scholar
  99. Pallagi P, Venglovecz V, Rakonczay Z, Jr, Borka K, Korompay A, Ozsvari B, Judak L, Sahin-Toth M, Geisz A, Schnur A, Maleth J, Takacs T, Gray MA, Argent BE, Mayerle J, Lerch MM, Wittmann T, Hegyi P (2011) Trypsin reduces pancreatic ductal bicarbonate secretion by inhibiting CFTR Cl(−) channels and luminal anion exchangers. Gastroenterology 141:2228–2239 e2226Google Scholar
  100. Pandol SJ, Periskic S, Gukovsky I, Zaninovic V, Jung Y, Zong Y, Solomon TE, Gukovskaya AS, Tsukamoto H (1999) Ethanol diet increases the sensitivity of rats to pancreatitis induced by cholecystokinin octapeptide. Gastroenterology 117:706–716PubMedGoogle Scholar
  101. Pandol SJ, Gorelick FS, Gerloff A, Lugea A (2010) Alcohol abuse, endoplasmic reticulum stress and pancreatitis. Dig Dis 28:776–782PubMedGoogle Scholar
  102. Pandol SJ, Lugea A, Mareninova OA, Smoot D, Gorelick FS, Gukovskaya AS, Gukovsky I (2011) Investigating the pathobiology of alcoholic pancreatitis. Alcohol Clin Exp Res 35:830–837PubMedGoogle Scholar
  103. Parekh AB, Putney JW Jr (2005) Store-operated calcium channels. Physiol Rev 85:757–810PubMedGoogle Scholar
  104. Park MK, Lomax RB, Tepikin AV, Petersen OH (2001) Local uncaging of caged Ca(2+) reveals distribution of Ca(2+)-activated Cl(−) channels in pancreatic acinar cells. Proc Natl Acad Sci USA 98:10948–10953PubMedGoogle Scholar
  105. Park M, Ko SB, Choi JY, Muallem G, Thomas PJ, Pushkin A, Lee MS, Kim JY, Lee MG, Muallem S, Kurtz I (2002) The cystic fibrosis transmembrane conductance regulator interacts with and regulates the activity of the HCO3 salvage transporter human Na+−HCO3 cotransport isoform 3. J Biol Chem 277:50503–50509PubMedGoogle Scholar
  106. Park HW, Nam JH, Kim JY, Namkung W, Yoon JS, Lee JS, Kim KS, Venglovecz V, Gray MA, Kim KH, Lee MG (2010) Dynamic regulation of CFTR bicarbonate permeability by [Cl]i and its role in pancreatic bicarbonate secretion. Gastroenterology 139:620–631PubMedGoogle Scholar
  107. Patel AG, Reber PU, Toyama MT, Ashley SW, Reber HA (1999) Effect of pancreaticojejunostomy on fibrosis, pancreatic blood flow, and interstitial pH in chronic pancreatitis: a feline model. Ann Surg 230:672–679PubMedGoogle Scholar
  108. Pazoles CJ, Pollard HB (1978) Evidence for stimulation of anion transport in ATP-evoked transmitter release from isolated secretory vesicles. J Biol Chem 253:3962–3969PubMedGoogle Scholar
  109. Peery AF, Dellon ES, Lund J, Crockett SD, McGowan CE, Bulsiewicz WJ, Gangarosa LM, Thiny MT, Stizenberg K, Morgan DR, Ringel Y, Kim HP, Dibonaventura MD, Carroll CF, Allen JK, Cook SF, Sandler RS, Kappelman MD, Shaheen NJ (2012) Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology 143(1179–1187):e1171–e1173Google Scholar
  110. Perides G, Laukkarinen JM, Vassileva G, Steer ML (2010) Biliary acute pancreatitis in mice is mediated by the G-protein-coupled cell surface bile acid receptor Gpbar1. Gastroenterology 138:715–725PubMedGoogle Scholar
  111. Petersen OH (1992) Stimulus-secretion coupling: cytoplasmic calcium signals and the control of ion channels in exocrine acinar cells. J Physiol 448:1–51PubMedGoogle Scholar
  112. Petersen OH (2005) Ca2+ signalling and Ca2+−activated ion channels in exocrine acinar cells. Cell Calcium 38:171–200PubMedGoogle Scholar
  113. Petersen OH (2008) Physiology of acinar cell secretion. In: Beger H (ed) The pancreas. Blackwell, San Diego, pp 71–78Google Scholar
  114. Petersen OH, Findlay I (1987) Electrophysiology of the pancreas. Physiol Rev 67:1054–1116PubMedGoogle Scholar
  115. Petersen OH, Maruyama Y (1984) Calcium-activated potassium channels and their role in secretion. Nature 307:693–696PubMedGoogle Scholar
  116. Petersen OH, Sutton R (2006) Ca2+ signalling and pancreatitis: effects of alcohol, bile and coffee. Trends Pharmacol Sci 27:113–120PubMedGoogle Scholar
  117. Petersen OH, Tepikin AV (2008) Polarized calcium signaling in exocrine gland cells. Annu Rev Physiol 70:273–299PubMedGoogle Scholar
  118. Petersen OH, Findlay I, Iwatsuki N, Singh J, Gallacher DV, Fuller CM, Pearson GT, Dunne MJ, Morris AP (1985) Human pancreatic acinar cells: studies of stimulus-secretion coupling. Gastroenterology 89:109–117PubMedGoogle Scholar
  119. Petersen OH, Tepikin AV, Gerasimenko JV, Gerasimenko OV, Sutton R, Criddle DN (2009) Fatty acids, alcohol and fatty acid ethyl esters: toxic Ca2+ signal generation and pancreatitis. Cell Calcium 45:634–642PubMedGoogle Scholar
  120. Petersen OH, Gerasimenko OV, Gerasimenko JV (2011a) Pathobiology of acute pancreatitis: focus on intracellular calcium and calmodulin. F1000 Med Rep 3:15PubMedGoogle Scholar
  121. Petersen OH, Gerasimenko OV, Tepikin AV, Gerasimenko JV (2011b) Aberrant Ca(2+) signalling through acidic calcium stores in pancreatic acinar cells. Cell Calcium 50:193–199PubMedGoogle Scholar
  122. Quinton PM (2001) The neglected ion: HCO3. Nat Med 7:292–293PubMedGoogle Scholar
  123. Racz GZ, Kittel A, Riccardi D, Case RM, Elliott AC, Varga G (2002) Extracellular calcium sensing receptor in human pancreatic cells. Gut 51:705–711PubMedGoogle Scholar
  124. Rakonczay Z Jr, Fearn A, Hegyi P, Boros I, Gray MA, Argent BE (2006) Characterization of H+ and HCO3 transporters in CFPAC-1 human pancreatic duct cells. World J Gastroenterol 12:885–895PubMedGoogle Scholar
  125. Raraty M, Ward J, Erdemli G, Vaillant C, Neoptolemos JP, Sutton R, Petersen OH (2000) Calcium-dependent enzyme activation and vacuole formation in the apical granular region of pancreatic acinar cells. Proc Natl Acad Sci USA 97:13126–13131PubMedGoogle Scholar
  126. Reber HA, Mosley JG (1980) The effect of bile salts on the pancreatic duct mucosal barrier. Br J Surg 67:59–62PubMedGoogle Scholar
  127. Reber HA, Roberts C, Way LW (1979) The pancreatic duct mucosal barrier. Am J Surg 137:128–134PubMedGoogle Scholar
  128. Regoli M, Bendayan M, Fonzi L, Sernia C, Bertelli E (2003) Angiotensinogen localization and secretion in the rat pancreas. J Endocrinol 179:81–89PubMedGoogle Scholar
  129. Rinderknecht H (1993) Pancreatic secretory enzymes. Raven, New YorkGoogle Scholar
  130. Rindler MJ, Xu CF, Gumper I, Smith NN, Neubert TA (2007) Proteomic analysis of pancreatic zymogen granules: identification of new granule proteins. J Proteome Res 6:2978–2992PubMedGoogle Scholar
  131. Rosendahl J, Witt H, Szmola R, Bhatia E, Ozsvari B, Landt O, Schulz HU, Gress TM, Pfutzer R, Lohr M, Kovacs P, Bluher M, Stumvoll M, Choudhuri G, Hegyi P, te Morsche RH, Drenth JP, Truninger K, Macek M Jr, Puhl G, Witt U, Schmidt H, Buning C, Ockenga J, Kage A, Groneberg DA, Nickel R, Berg T, Wiedenmann B, Bodeker H, Keim V, Mossner J, Teich N, Sahin-Toth M (2008) Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet 40:78–82PubMedGoogle Scholar
  132. Sahin-Toth M, Toth M (2000) Gain-of-function mutations associated with hereditary pancreatitis enhance autoactivation of human cationic trypsinogen. Biochem Biophys Res Commun 278:286–289PubMedGoogle Scholar
  133. Sarles H, Sarles JC, Camatte R, Muratore R, Gaini M, Guien C, Pastor J, Le Roy F (1965) Observations on 205 confirmed cases of acute pancreatitis, recurring pancreatitis, and chronic pancreatitis. Gut 6:545–559PubMedGoogle Scholar
  134. Scheele GA, Fukuoka SI, Kern HF, Freedman SD (1996) Pancreatic dysfunction in cystic fibrosis occurs as a result of impairments in luminal pH, apical trafficking of zymogen granule membranes, and solubilization of secretory enzymes. Pancreas 12:1–9PubMedGoogle Scholar
  135. Sherwood MW, Prior IA, Voronina SG, Barrow SL, Woodsmith JD, Gerasimenko OV, Petersen OH, Tepikin AV (2007) Activation of trypsinogen in large endocytic vacuoles of pancreatic acinar cells. Proc Natl Acad Sci USA 104:5674–5679PubMedGoogle Scholar
  136. Simon P, Weiss FU, Sahin-Toth M, Parry M, Nayler O, Lenfers B, Schnekenburger J, Mayerle J, Domschke W, Lerch MM (2002) Hereditary pancreatitis caused by a novel PRSS1 mutation (Arg-122 –> Cys) that alters autoactivation and autodegradation of cationic trypsinogen. J Biol Chem 277:5404–5410PubMedGoogle Scholar
  137. Singh M, LaSure MM, Bockman DE (1982) Pancreatic acinar cell function and morphology in rats chronically fed an ethanol diet. Gastroenterology 82:425–434PubMedGoogle Scholar
  138. Suzuki A, Naruse S, Kitagawa M, Ishiguro H, Yoshikawa T, Ko SB, Yamamoto A, Hamada H, Hayakawa T (2001) 5-hydroxytryptamine strongly inhibits fluid secretion in guinea pig pancreatic duct cells. J Clin Invest 108:749–756PubMedGoogle Scholar
  139. Szucs A, Demeter I, Burghardt B, Ovari G, Case RM, Steward MC, Varga G (2006) Vectorial bicarbonate transport by Capan-1 cells: a model for human pancreatic ductal secretion. Cell Physiol Biochem 18:253–264PubMedGoogle Scholar
  140. Tahmasebi M, Puddefoot JR, Inwang ER, Vinson GP (1999) The tissue renin-angiotensin system in human pancreas. J Endocrinol 161:317–322PubMedGoogle Scholar
  141. Thevenod F (2002) Ion channels in secretory granules of the pancreas and their role in exocytosis and release of secretory proteins. Am J Physiol Cell Physiol 283:C651–C672PubMedGoogle Scholar
  142. Thevenod F, Kemmer TP, Christian AL, Schulz I (1989) Characterization of MgATP-driven H+ uptake into a microsomal vesicle fraction from rat pancreatic acinar cells. J Membr Biol 107:263–275PubMedGoogle Scholar
  143. Thevenod F, Roussa E, Benos DJ, Fuller CM (2003) Relationship between a HCO3 -permeable conductance and a CLCA protein from rat pancreatic zymogen granules. Biochem Biophys Res Commun 300:546–554PubMedGoogle Scholar
  144. Thrower EC, Gorelick FS, Husain SZ (2010) Molecular and cellular mechanisms of pancreatic injury. Curr Opin Gastroenterol 26:484–489PubMedGoogle Scholar
  145. Topazian M, Pandol S (2009) Acute pancreatitis. In: Yamada T (ed) Textbook of gastroenterology, vol 2. Wiley-Blackwell, Oxford, pp 1761–1811Google Scholar
  146. Toyama MT, Patel AG, Nguyen T, Ashley SW, Reber HA (1997) Effect of ethanol on pancreatic interstitial pH and blood flow in cats with chronic pancreatitis. Ann Surg 225:223–228PubMedGoogle Scholar
  147. Venglovecz V, Rakonczay Z Jr, Ozsvari B, Takacs T, Lonovics J, Varro A, Gray MA, Argent BE, Hegyi P (2008) Effects of bile acids on pancreatic ductal bicarbonate secretion in guinea pig. Gut 57:1102–1112PubMedGoogle Scholar
  148. Venglovecz V, Hegyi P, Rakonczay Z Jr, Tiszlavicz L, Nardi A, Grunnet M, Gray MA (2011a) Pathophysiological relevance of apical large-conductance Ca(2)+−activated potassium channels in pancreatic duct epithelial cells. Gut 60:361–369PubMedGoogle Scholar
  149. Venglovecz V, Judák L, Rakonczay Z, Gray M, Hegyi P (2011b) Effects of ethanol and its non-oxidative metabolites on CFTR activity in guinea pig pancreatic duct cells. Gut 60:A363Google Scholar
  150. Venglovecz V, Rakonczay Z Jr, Hegyi P (2012) The effects of bile acids on pancreatic ductal cells. Pancreapedia 1–8Google Scholar
  151. Voronina S, Longbottom R, Sutton R, Petersen OH, Tepikin A (2002) Bile acids induce calcium signals in mouse pancreatic acinar cells: implications for bile-induced pancreatic pathology. J Physiol 540:49–55PubMedGoogle Scholar
  152. Voronina SG, Barrow SL, Gerasimenko OV, Petersen OH, Tepikin AV (2004) Effects of secretagogues and bile acids on mitochondrial membrane potential of pancreatic acinar cells: comparison of different modes of evaluating DeltaPsim. J Biol Chem 279:27327–27338PubMedGoogle Scholar
  153. Voronina SG, Barrow SL, Simpson AW, Gerasimenko OV, da Silvia Xavier G, Rutter GA, Petersen OH, Tepikin AV (2010) Dynamic changes in cytosolic and mitochondrial ATP levels in pancreatic acinar cells. Gastroenterology 138:1976–1987PubMedGoogle Scholar
  154. Walters MN (1965) Goblet-cell metaplasia in ductules and acini of the exocrine pancreas. J Pathol Bacteriol 89:569–572PubMedGoogle Scholar
  155. Wang Y, Soyombo AA, Shcheynikov N, Zeng W, Dorwart M, Marino CR, Thomas PJ, Muallem S (2006) Slc26a6 regulates CFTR activity in vivo to determine pancreatic duct HCO3 secretion: relevance to cystic fibrosis. EMBO J 25:5049–5057PubMedGoogle Scholar
  156. Wang Y, Sternfeld L, Yang F, Rodriguez JA, Ross C, Hayden MR, Carriere F, Liu G, Hofer W, Schulz I (2009) Enhanced susceptibility to pancreatitis in severe hypertriglyceridaemic lipoprotein lipase-deficient mice and agonist-like function of pancreatic lipase in pancreatic cells. Gut 58:422–430PubMedGoogle Scholar
  157. Werner J, Laposata M, Fernandez-del Castillo C, Saghir M, Iozzo RV, Lewandrowski KB, Warshaw AL (1997) Pancreatic injury in rats induced by fatty acid ethyl ester, a nonoxidative metabolite of alcohol. Gastroenterology 113:286–294PubMedGoogle Scholar
  158. Whitcomb DC, Lowe ME (2007) Human pancreatic digestive enzymes. Dig Dis Sci 52:1–17PubMedGoogle Scholar
  159. Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, Martin SP, Gates LK Jr, Amann ST, Toskes PP, Liddle R, McGrath K, Uomo G, Post JC, Ehrlich GD (1996) Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 14:141–145PubMedGoogle Scholar
  160. Witt H, Luck W, Hennies HC, Classen M, Kage A, Lass U, Landt O, Becker M (2000) Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 25:213–216PubMedGoogle Scholar
  161. Wright AM, Gong X, Verdon B, Linsdell P, Mehta A, Riordan JR, Argent BE, Gray MA (2004) Novel regulation of cystic fibrosis transmembrane conductance regulator (CFTR) channel gating by external chloride. J Biol Chem 279:41658–41663PubMedGoogle Scholar
  162. Yamamoto A, Ishiguro H, Ko SB, Suzuki A, Wang Y, Hamada H, Mizuno N, Kitagawa M, Hayakawa T, Naruse S (2003) Ethanol induces fluid hypersecretion from guinea-pig pancreatic duct cells. J Physiol 551:917–926PubMedGoogle Scholar
  163. Yang F, Wang Y, Sternfeld L, Rodriguez JA, Ross C, Hayden MR, Carriere F, Liu G, Schulz I (2009) The role of free fatty acids, pancreatic lipase and Ca+ signalling in injury of isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice. Acta Physiol (Oxf) 195:13–28Google Scholar
  164. Yegutkin GG, Samburski SS, Jalkanen S, Novak I (2006) ATP-consuming and ATP-generating enzymes secreted by pancreas. J Biol Chem 281:29441–29447PubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.First Department of MedicineUniversity of SzegedSZEGEDHungary
  2. 2.MRC Group, School of BiosciencesCardiff UniversityWalesUK

Personalised recommendations