The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지

Molecular Mechanism of Pancreatic Bicarbonate Secretion

  • Lee, Min-Goo (Department of Pharmacology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine) ;
  • Kim, Je-Woo (Department of Pharmacology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine) ;
  • Kim, Kyung-Hwan (Department of Pharmacology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine) ;
  • Muallem, Shmuel (Department of Pharmacology, University of Texas Southwestern Medical Center)
  • Published : 2002.06.21
Download PDF
⟨ Previous Next ⟩

Abstract

Thanks to recent progress in availability of molecular and functional techniques it became possible to search for the basic molecular and cellular processes that mediate and control $HCO_3{^-}$ and fluid secretion by the pancreatic duct. The coordinated action of various transporters on the luminal and basolateral membranes of polarized epithelial cells mediates the transepithelial $HCO_3{^-}$ transport, which involves $HCO_3{^-}$ absorption in the resting state and $HCO_3{^-}$ secretion in the stimulated state. The overall process of HCO3 secretion can be divided into two steps. First, $HCO_3{^-}$ in the blood enters the ductal epithelial cells across the basolateral membrane either by simple diffusion in the forms of $CO_2$ and $H_2O$ or by the action of an $Na^+-coupled$ transporter, a $Na^+-HCO_3$ cotranporter (NBC) identified as pNBC1. Subsequently, the cells secrete $HCO_3{^-}$ to the luminal space using at least two $HCO_3{^-}$ exit mechanisms at the luminal membrane. One of the critical transporters needed for all forms of $HCO_3{^-}$ secretion across the luminal membrane is the cystic fibrosis transmembrane conductance regulator (CFTR). In the resting state the pancreatic duct, and probably other $HCO_3{^-}$ secretory epithelia, absorb $HCO_3{^-}.$ Interestingly, CFTR also control this mechanism. In this review, we discuss recent progress in understanding epithelial $HCO_3{^-}$ transport, in particular the nature of the luminal transporters and their regulation by CFTR.

Keywords

References

  1. Abuladze N, Lee I, Newman D, Hwang J, Boorer K, Pushkin A, Kurtz I. Molecular cloning, chromosomal localization, tissue distribution, and functional expression of the human pancreatic sodium bicarbonate cotransporter. J Biol Chem 273: 17689－ 17695, 1998 https://doi.org/10.1074/jbc.273.28.17689
  2. Ahn W, Kim KH, Lee JA, Kim JY, Choi JY, Moe OW, Milgram SL, Muallem S, Lee MG. Regulatory interaction between CFTR and HCO3 - salvage mechanisms in model systems and the mouse pancreatic duct. J Biol Chem 276: 17236－17243, 2001 https://doi.org/10.1074/jbc.M011763200
  3. Argent BE, Case RM. Pancreatic ducts. Cellular mechanism and control of bicarbonate secretion. In Johson LR et al, Physiology of the Gastrointestinal tract. 3 rd ed. Chapter 40., Raven Press, New York, 1994, pp 1473－1497
  4. Bagorda A, Guerra L, Di Sole F, Hemle-Kolb C, Cardone RA, Fanelli T, Reshkin SJ, Gisler SM, Murer H, Casavola V. Reciprocal PKA regulatory interactions between CFTR and NHE3 in a renal polarized epithelial cell model. J Biol Chem 2002 Apr 5 [epub ahead of print]
  5. Choi I, Aalkjaer C, Boulpaep EL, Boron WF. An electroneutral sodium/bicarbonate cotransporter NBCn1 and associated sodium channel. Nature 405: 571－575, 2000 https://doi.org/10.1038/35014615
  6. Choi JY, Muallem D, Kiselyov K, Lee MG, Thomas PJ, Muallem S. Aberrant CFTR-dependent HCO$_3$ - transport in mutations associated with cystic fibrosis. Nature 410: 94－97, 2001 https://doi.org/10.1038/35065099
  7. Choi JY, Shah M, Lee MG, Schultheis PJ, Shull GE, Muallem S, Baum M. Novel amiloride-sensitive sodium-dependent proton secretion in the mouse proximal convoluted tubule. J Clin Invest 105: 1141－1146, 2000 https://doi.org/10.1172/JCI9260
  8. Everett LA, Glaser B, Beck JC, Idol JR, Buchs A, Heyman M, Adawi F, Hazani E, Nassir E, Baxevanis AD, Sheffield VC, Green ED. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet 17: 411－ 422, 1997 https://doi.org/10.1038/ng1297-411
  9. Ishiguro H, Naruse S, Steward MC, Kitagawa M, Ko SB, Hayakawa T, Case RM. Fluid secretion in interlobular ducts isolated from guinea-pig pancreas. J Physiol 511: 407－422, 1998 https://doi.org/10.1111/j.1469-7793.1998.407bh.x
  10. Kim E, Niethammer M, Rothschild A, Jan YN, Sheng M. Clustering of Shaker-type K$^+$ channels by interaction with a family of membrane-associated guanylate kinases. Nature 378: 85－88, 1995 https://doi.org/10.1038/378085a0
  11. Knauf F, Yang CL, Thomson RB, Mentone SA, Giebisch G, Aronson PS. Identification of a chloride-formate exchanger expressed on the brush border membrane of renal proximal tubule cells. Proc Natl Acad Sci USA 98: 9425－9430, 2001 https://doi.org/10.1073/pnas.141241098
  12. Ko SB, Choi JY, Lee MG, Thomas PJ, Muallem S. A molecular mechanism for aberrant CFTR dependent bicarbonate transport. Experimental Biology 2002 Abst. 632.3
  13. Lee MG, Ahn W, Choi JY, Luo X, Seo JT, Schultheis PJ, Shull GE, Kim KH, Muallem S. Na$^+$-dependent transporters mediate HCO$_3$ - salvage across the luminal membrane of the main pancreatic duct. J Clin Invest 105: 1651－1658, 2000 https://doi.org/10.1172/JCI9207
  14. Lee MG, Ahn W, Lee JA, Kim JY, Choi JY, Moe OW, Milgram SL, Muallem S, Kim KH. Coordination of pancreatic HCO$_3$ - secretion by protein-protein interaction between membrane transporters. J Pancreas 2: S203－S206, 2001
  15. Lee MG, Choi JY, Luo X, Strickland E, Thomas PJ, Muallem S. Cystic fibrosis transmembrane conductance regulator regulates luminal Cl-/HCO$_3$ - exchange in mouse submandibular and pancreatic ducts. J Biol Chem 274: 14670－14677, 1999b https://doi.org/10.1074/jbc.274.21.14670
  16. Lee MG, Schultheis PJ, Yan M, Shull GE, Bookstein C, Chang E, Tse M, Donowitz M, Park K, Muallem S. Membrane-limited expression and regulation of Na$^+$-H$^+$ exchanger isoforms by P2 receptors in the rat submandibular gland duct. J Physiol 513: 341－357, 1998 https://doi.org/10.1111/j.1469-7793.1998.341bb.x
  17. Lee MG, Wigley WC, Zeng W, Noel LE, Marino CR, Thomas PJ, Muallem S. Regulation of Cl$^-$/HCO$_3$$^-$ - exchange by cystic fibrosis transmembrane conductance regulator expressed in NIH 3T3 and HEK 293 cells. J Biol Chem 274: 3414－3421, 1999a https://doi.org/10.1074/jbc.274.6.3414
  18. Luo X, Choi JY, Ko SB, Pushkin A, Kurtz I, Ahn W, Lee MG, Muallem S. HCO$_3$$^-$ salvage mechanisms in the submandibular gland acinar and duct cells. J Biol Chem 276: 9808－9816, 2001 https://doi.org/10.1074/jbc.M008548200
  19. Michel JJ, Scott JD. AKAP mediated signal transduction. Annu Rev Pharmacol Toxicol 42: 235－57, 2002 https://doi.org/10.1146/annurev.pharmtox.42.083101.135801
  20. Miyazaki E, Sakaguchi M, Wakabayashi S, Shigekawa M, Mihara K. NHE6 protein possesses a signal peptide destined for endoplasmic reticulum membrane and localizes in secretory organelles of the cell. J Biol Chem 276: 49221－49227, 2001 https://doi.org/10.1074/jbc.M106267200
  21. Raghuram V, Mak DD, Foskett JK. Regulation of cystic fibrosis transmembrane conductance regulator single-channel gating by bivalent PDZ-domain-mediated interaction. Proc Natl Acad Sci USA 98: 1300－1305, 2001 https://doi.org/10.1073/pnas.031538898
  22. Royaux IE, Wall SM, Karniski LP, Everett LA, Suzuki K, Knepper MA, Green ED. Pendrin, encoded by the Pendred syndrome gene, resides in the apical region of renal intercalated cells and mediates bicarbonate secretion. Proc Natl Acad Sci USA 98: 4221－4226, 2001 https://doi.org/10.1073/pnas.071516798
  23. Schultheis PJ, Clarke LL, Meneton P, Harline M, Boivin GP, Stemmermann G, Duffy JJ, Doetschman T, Miller ML, Shull GE. Targeted disruption of the murine Na$^+$/H$^+$ exchanger isoform 2 gene causes reduced viability of gastric parietal cells and loss of net acid secretion. J Clin Invest 101: 1243－1253, 1998 https://doi.org/10.1172/JCI1249
  24. Silberg DG, Wang W, Moseley RH, Traber PG. The Down regulated in Adenoma (dra) gene encodes an intestine-specific membrane sulfate transport protein. J Biol Chem 270: 11897－11902, 1995 https://doi.org/10.1074/jbc.270.20.11897
  25. Sohma Y, Gray MA, Imai Y, Argent BE. HCO$_3$ $^-$ transport in a mathematical model of the pancreatic ductal epithelium. J Membr Biol 176: 77－100, 2000 https://doi.org/10.1007/s002320001077
  26. Wang S, Yue H, Derin RB, Guggino WB, Li M. Accessory protein facilitated CFTR-CFTR interaction, a molecular mechanism to potentiate the chloride channel activity. Cell 103: 169－179, 2000 https://doi.org/10.1016/S0092-8674(00)00096-9
  27. Zhao H, Star RA, Muallem S. Membrane localization of H$^+$ and HCO$_3$ $^-$ transporters in the rat pancreatic duct. J Gen Physiol 104: 57－85, 1994 https://doi.org/10.1085/jgp.104.1.57