Abstract
Ten years ago, the basic principles operating in one specific, albeit non-mammalian, exocrine gland, the rectal gland of Squalus acanthias, were described in detail. The concept emerging from these studies appeared applicable to almost any other exocrine gland, because it involved membrane transporters which are also present in mammalian epithelial cells. Meanwhile, it has become clear that the mechanisms of NaCl secretion are diverse: the mechanisms of NaCl uptake; the ion channels involved; and also the mechanisms of hormonal control. Nevertheless, several steps in NaCl secretion still appear to be uniform: (1) several signalling pathways converge and act cooperatively, (2) one primary regulatory step is the upregulation of the luminal Cl− conductance, (3) secondarily active NaCl uptake mechanisms are upregulated, (4) increasing evidence links NaCl secretion to membrane trafficking and (5) the entire machinery seems to be primed to secure cellular homeostasis in terms of cytosolic ion concentrations. This brief review summarizes the mechanisms of control of NaCl secretion. The major issues addressed are the NaCl uptake mechanisms, the ion channels involved and the cellular mechanisms coordinating secretion. The major NaCl secreting cells discussed here will be the respiratory epithelial cells, the exocrine cells of pancreatic acini and the cells of colonic crypts.
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Anderson MP, Welsh MJ (1991) Calcium and cAMP activate different chloride channels in the apical membrane of normal and cystic fibrosis epithelia. Proc Natl Acad Sic USA 88:6003–6007
Anderson MP, Gregory RJ, Thompson S, Souza DW, Paul S, Mulligan RC, Smith AE, Welsh MJ (1991) Demonstration that CFTR is a chloride channel by alternation of its anion selectivity. Science 253:202–205
Bear CE, Li C, Kartner N, Bridges RJ, Jensen TJ, Ramjeesingh M, Riordan JR (1992) Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR). Cell 68:809–818
Bijman J, Dalemans W, Kansen M, Keulemans J, Verbeek E, Hoogeveen A, De Jonge H, Wilke M, Dreyer D, Lecocq JP, Pavirani A, Scholte B (1993) Low-conductance chloride channels in IEC-6 and CF nasal cells expressing CFTR. Am J Physiol 264:L229-L235
Boucher RC, Cotton CU, Gatzy JT, Knowles MR, Yankaskas JR (1988) Evidence for reduced Cl− and increased Na+ permeability in cystic fibrosis human primary cell cultures. J Physiol (Lond) 405:77–103
Bradbury NA, Jilling T, Berta G, Sorscher EJ, Bridges RJ, Kirk KL (1992) Regulation of plasma membrane recycling by CFTR. Science 256:530–532
Burckhardt BC, Gögelein H (1992) Small and maxi K+ channels in the basolateral membrane of isolated crypts from rat distal colon. Pflügers Arch 420:54–60
Cliff WH, Frizzell RA (1990) Separate Cl− conductances activated by cAMP and Ca2+ in Cl− secreting epithelial cells. Proc Natl Acad Sci USA 87:4956–4960
Cliff WH, Schoumacher RA, Frizzell RA (1992) cAMP-activated Cl channels in CFTR-transfected cystic fibrosis pancreatic epithelial cells. Am J Physiol 262:C1154-C1160
Cunningham SA, Worrell RT, Benos D, Frizzell RA (1992) cAMP-stimulated ion currents in Xenopus oocytes expressing CFTR cRNA. Am J Physiol 262:C783-C788
Dalemans W, Barbry P, Champigny G, Jallat S, Dott K, Dreyer D, Crystal RG, Pavirani A, Lecocq JP, Lazdunski M (1991) Altered chloride channel kinetics associated with the AF 508 cystic fibrosis mutation. Nature 354:526–528
Dharmasathaphorn K, Mandel KG, Masui H, McRoberts JA (1985) Vasoactive intestinal polypeptide-induced chloride secretion by a colonic epithelial cell line. Direct participation of a basolaterlaly localized Na+, K+, Cl− co-transport system. J Clin Invest 75:462–471
Diener M, Rummel W, Mestres P, Lindemann B (1989) Single chloride channels in colon mucosa and isolated enterocytes of the rat. J Membr Biol 108:21–30
Disser J, Hazama A, Frömter E (1993) Chloride channel studies on HT29 cells with minimal levels of cAMP-mediated stimulation (abstract). Pflügers Arch 422:R65
Ecke D, Bleich M, Lohrmann E, Hropot M, Englert HC, Lang HJ, Warth R, Rohm W, Schwartz B, Fraser G, Greger R (1995) A chromanol type of K+ channel blocker inhibits forskolin- but not carbachol-mediated Cl− secretion in rat and rabbit colon. Cell Physiol Biochem 5:204–210
Ecke D, Bleich M, Greger R (1996) Crypt base cells show forskolin-induced Cl− secretion but no cation inward current. Pflügers Arch 431:427–434
Frizzell RA, Rechkemmer GR, Shoemaker RL (1986) Altered regulation of airway epithelial cell chloride channels in cystic fibrosis. Science 233:558–560
Fuller CM, Benos DJ (1992) CFTR! Am J Physiol 267: C267–287
Gamba G, Slatzberg SN, Lombardi M, Miyanoshita A, Lytton J, Hediger MA, Brenner BM, Hebert SC (1993) Primary structure and functional expression of a cDNA encoding the thiazide-sensitive, electroneutral sodium-chloride cotransporter. Proc Natl Acad Sci USA 90:2749–2753
Gamba G, Miyanoshita A, Lombardi M, Lytton J, Lee WS, Hediger MA, Hebert SC (1994) Molecular cloning, primary structure, and characterization of two members of the mammalian electroneutral sodium-(potassium)-chloride cotransporter family expressed in kidney. J Biol Chem 269: 17713–17722
Gilmore JP, Dietz J, Gilmore C, Zucker IH (1977) Evidence for a chloride pump in the salt gland of the goose. Comp Biochem Physiol A56:121–126
Gögelein H, Schlatter E, Greger R (1987) The “small” conductance chloride channel in the luminal membrane of the rectal gland of the dogfish (Squalus acanthias). Pflügers Arch 409:122–125
Greger R (1994) Chloride channels of colonic carcinoma cells. In: Peracchia C (ed) Hundbook of membrane channels. Academic Press, San Diego, pp 229–244
Greger R, Schlatter E (1981) Presence of luminal K+, a prerequisite for active NaCl transprot in the thick ascending limb of Henle’s loop of rabbit kidney. Pflügers Arch 392: 92–94
Greger R, Schlatter E (1984) Mechanism of NaCl secretion in the rectal gland of spiny dogfish (Squalus acanthias). 1. Experiments in isolated in vitro perfused rectal gland tubules. Pflügers Arch 402:63–75
Greger R, Velázquez H (1987) The cortical thick ascending limb and early distal convoluted tubule in the urinary concentrating mechanism. Kidney Int 31:590–596
Greger R, Schlatter E, Wang F, Forrest JNJ (1984) Mechanism of NaCl secretion in rectal gland tubules of spiny dogfish (Squalus acanthias) III. Effects of stimulation of secretion by cyclic AMP. Pflügers Arch 402:376–384
Greger R, Schlatter E, Gögelein H (1986) Sodium chloride secretion in rectal gland of dogfish Squalus acanthias. News Physiol Sci 1:134–136
Greger R, Schlatter E, Gögelein H (1987) Chloride channels in the luminal membrane of the rectal gland of the dogfish (Squalus acanthias). Properties of the “larger” conductance channel. Pflügers Arch 409:114–121
Greger R, Kunzelmann K (1991) Simultaneous recording of the cell membrane potential and properties of the cell attached membrane of HT29 colon carcinoma and CF-PAC cells. Pflügers Arch 419:209–211
Greger R, Allert N, Fröbe U, Normann C (1993) Increase in cytosolic Ca2+ regulates exocytosis and Cl−-conductance in HT29 cells. Pflügers Arch 424:329–334
Haas M, McBrayer D, Lytle C (1995) [Cl− i-dependent phosphorylation of the Na-K-Cl cotransport protein of dog tracheal epithelial cells. J Biol Chem 270:28955–28961
Halm DR, Halm ST, DiBona DR, Frizzell RA, Johnson RD (1995) Selective stimulation of epithelial cells in colonie crypts: relation to active chloride secretion. Am J Physiol 269: C929-C942
Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflügers Arch 391:85–100
Hayslett JP, Gögelein H, Kunzelmann K, Greger R (1987) Characteristics of apical chloride channels in human colon cells (HT29). Pflügers Arch 410:487–494
Heintze K, Stewart CP, Frizzell RA (1983) Sodium-dependent chloride secretion across rabbit descending colon. Am J Physiol 244:G357-G365
Hipper A, Mall M, Greger R, Kunzelmann K (1995) Mutations in the putative pore-forming domain of CFTR do not change anion selectivity of the cAMP activated Cl− conductance FEBS Lett 374:312–316
Hug T, Koslowsky T, Ecke D, Greger R, Kunzelmann K (1995) Actin-dependent activation of ion conductances in bronchial epithelial cells. Pflügers Arch 429:682–690
Hwang TC, Lu L, Zeitlin L, Gruenert DC, Huganir R, Guggino WB (1989) Cl-channels in CF: lack of activation by protein kinase C and cAMP-dependent protein kinase. Science 244: 1351–1353
Kasai H, Augustine GJ (1990) Cytosolic Ca2+ gradients triggering unidirectional fluid secretion from exocrine pancreas. Nature 348:735–738
Klaerke DA, Wiener H, Zeuthen T, Jorgensen PL (1993) Ca2+ activation and pH dependence of a maxi K+ channel from rabbit distal colon epithelium. J Membr Biol 136:9–21
Kopelmann H, Ferretti E, Gauthier C, Goodyer PR (1995) Rabbit pancreatic acini express CFTR as a cAMP-activated chloride efflux pathway. Am J Physiol 269:C626-C631
Köttgen M, Leipziger J, Fischer KG, Greger R (1994) pH regulation in HT29 colon carcinoma cells. Pflügers Arch 428: 179–185
Krick W, Disser J, Hazama A, Burckhardt G, Frömter E(1991) Evidence for a cytosolic inhibitor of epithelial chloride channels. Pflügers Arch 418:491–499
Krick W, Disser J, Rabe A, Frömter E, Hansen CP, Roch B, Kunzelmann K, Greger R, Fehlhaber HW, Burckhardt G (1995) Characterization of cytosolic Cl− channel inhibitors by size exclusion chromatography. Cell Physiol Biochem 5: 259–268
Kubitz R, Warth R, Allert N, Kunzelmann K, Greger R (1992) Small conductance chloride channels induced by cAMP, Ca2+, and hypotonicity in HT29 cells: ion selectivity, additivity, and stilbene sensitivity. Pflügers Arch 421:447–454
Kunzelmann K, Pavenstädt H, Beck C, Ünal Ö, Emmrich P, Arndt HJ, Greger R (1989) Characterization of potassium channels in respiratory cells I. General properties. Pflügers Arch 414:291–296
Kunzelmann K, Pavenstädt H, Greger R (1989) Properties and regulation of chloride channels in cystic fibrosis and normal airway cells. Pflügers Arch 415:172–182
Kunzelmann K, Tilmann M, Hansen CP, Greger R (1991) Inhibition of epithelial chloride channels by cytosol. Pflügers Arch 418:479–490
Kunzelmann K, Tilmann M, Greger R (1992) Ion transport in HT29 colonic carcinoma cells. Adv Comp Envir Physiol 16: 237–251
Kunzelmann K, Grolik M, Kubitz R, Greger R (1992) cAMP- dependent activation of small-conductance Cl− channels in HT29 colon carcinoma cells. Pflügers Arch 421:230–237
Kunzelmann K, Koslowsky T, Hug T, Gruenert DC, Greger R (1994) cAMP-dependent activation of ion conductances in bronchial epithelial cells. Pflügers Arch 428:590–596
Kunzelmann K, Slotki IN, Klein P, Koslowsky T, Ausiello DA, Greger R, Cabantchik ZI (1994) Effects of P-glycoprotein expression on cyclic AMP and volume-activated ion fluxes and conductances in HT29 colon adenocarcinoma cells. J Cell Physiol 161:393–406
Kunzelmann K, Kathöfer S, Greger R (1995) Na+ and Cl− conductances in airway epithelial cells: increased Na+ conductances in cystic fibrosis. Pflügers Arch 431:1–9
Latorre R (1994) Molecular workings of large conductance (maxi) Ca2+-activated K+ channels. In: Peracchia C (ed) Handbook of membrane channels. Academic Press, San Diego, pp 79–104
Leipziger J, Fischer KG, Greger R (1994) Voltage dependent Ca2+ influx in the epithelial cell line HT29: simultaneous use of intracellular Ca2+ measurements and nystatin perforated patchclamp. Pflügers Arch 426:427–432
Li M, McCann JD, Liedtke CM, Nairn AC, Greengard P, Welsh MJ (1988) Cyclic AMP-dependent protein kinase opens chloride channels in normal but not cystic fibrosis airway epithelium. Nature 331:358–360
Liedtke CM (1989) Regulation of chloride transport in epithelia. Annu Rev Physiol 51:143–160
Liedtke CM (1990) Calcium and alpha-adrenergic regulation of Na-Cl(K) cotransport in rabbit tracheal epithelial cells. Am J Physiol 259:L66-L72
Lohrmann E, Burhoff I, Nitschke RB, Lang HJ, Mania D, Englert HC, Hropot M, Warth R, Rohm W, Bleich M, Greger R (1995) A new class of inhibitors of cAMP-mediated Cl− secretion in rabbit colon, acting by the reduction of cAMP-activated K+ conductance. Pflügers Arch 429:517–530
Lohrmann E, Greger R (1993) Isolated perfused rabbit colon crypts: stimulation of Cl− secretion by forskolin. Pflügers Arch 425:373–380
Lytle C, Xu JC, Biemesderfer D, Forbush B (1995) Distribution and diversity of Na-K-Cl cotransport proteins: a study with monoclonal antibodies. Am J Physiol 269:C1496-C1505
Mall M, Hipper A, Greger R, Kunzelmann K (1996) Wild type CFTR but not A F508 inhibitors Na+ channels in Xenopus oocytes. FEBS Lett 1381:47–52
Mall M, Kunzelmann K, Hipper A, Busch AE, Greger R (1996) Overexpression and cAMP stimulation of CFTR in Xenopus oocytes activates a chromanol inhibitable K+ conductance. Pflügers Arch (in press)
Marty A, Tan YP, Trautmann A (1984) Three types of calcium-dependent channel in rat lacrimal glands. J Physiol (Lond) 357:293–325
Maruyama Y, Inooka G, Li YX, Miyashita Y, Kasai H (1993) Agonist-induced localized Ca2+ spikes directly triggering exocytotic secretion in exocrine pancreas. EMBO J 12:3017–3022
Marver D (1990) Aldosterone. Methods Enzymol 191:520–550
McCann JD, Welsh MJ (1990) Regulation of Cl− and K+ channels in airway epithelium. Annu Rev Physiol 52:115–135
Payne JA, Xu JC, Haas M, Lytle CY, Ward D, Forbush B (1995) Primary structure, functional expression, and chromosomal localization of the bumetanide-sensitive Na-K-Cl cotransporter in human colon. J Biol Chem 270:17977–17985
Petersen OH (1992) Stimulus-secretion coupling: cytoplasmic calcium signals and the control of ion channels in exocrine acinar cells. J Physiol (Lond) 448:1–51
Pirani D, Evans LAR, Cook DI, Young JA (1987) Intracellular pH in the rat mandibular salivary gland: the role of Na-H and Cl-HCO3 antiports in secretion. Pflügers Arch 408:178–184
Rich DP, Anderson MP, Gregory RJ, Cheng SH, Paul S, Jefferson DM, McCann JD, Klinger KW, Smith AE, Welsh MJ (1990) Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells. Nature 347:358–363
Bleich M, Riedemann N, Warth R, Hör M, Van Driessche W, Greger R (1996) Ca2+ regulated K+ and non-selective channels in the baso-lateral membrane of rat colonic crypt base cells. Pflügers Arch (in press)
Riordan JR (1993) The cystic fibrosis transmembrane conductance regulator. Annu Rev Physiol 55:609–630
Riordan JR, Rommens JM, Kerem B-S, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou J-L, Drumm ML, Iannuzzi MC, Collins FS, Tsui L-C (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245:1066–1073
Robertson MA, Foskett JK (1994) Na+ transport pathways in secretory acinar cells: membrane cross talk mediated by [Cl−]1. Am J Physiol 267:C146-C156
Rohlicek V, Schmid A (1994) Dual-frequency method for synchronous measurement of cell capacitance, membrane conductance and access resistance on single cells. Pflügers Arch 428: 30–38
Sandle GI, McNicholas CM, Lomax RB (1994) Potassium channels in colonic crypts. Lancet 343:23–25
Schlatter E, Greger R (1988) NaCl transport in salt glands. In: Greger R (ed) Advances in Comparative and Environmental Physiology, vol. 1, Springer, Berlin Heidelberg New York, pp 273–290
Schlatter E, Greger R, Weidtke C (1983) Effect of “high ceiling” diuretics on active salt transport in the cortical thick ascending limb of Henle’s loop of rabbit kidney. Correlation of chemical structure and inhibitory potency. Pflügers Arch 396:210–217
Schmid A, Schulz I (1995) Characterization of single potassium channels in mouse pancreatic acinar cells. J Physiol (Lond) 484.3:661–676
Schwiebert EM, Egan ME, Hwang TH, Fulmer SB, Allen SS, Cutting GR, Guggino WB (1995) CFTR regulates outwardly rectifying chloride channels through an autocrine mechanism involving ATP. Cell 81:1063–1073
Seibert FS, Tabcharani JA, Chang XB, Dulhanty AM, Mathews C, Hanrahan JW, Riordan JR (1995) cAMP-dependent protein kinase-mediated phosphorylation of cystic fibrosis transmembrane conductance regulator residue Ser-753 and its role in channel activation. J Biol Chem 270:2158–2162
Slawik M, Zdebik A, Hug MJ, Kerstan D, Leipziger J, Greger R (1996) Whole cell conductive properties of rat pancreatic acini. Pflügers Arch 432:112–120
Stutts MJ, Fitz JG, Paradiso AM, Boucher RC (1994) Multiple modes of regulation of airway epithelial chloride secretion by extracellular ATP. AM J Physiol 267:C1442-C1451
Tabcharani JA, Low W, Elie D, Hanrahan JW (1990) Lowconductance chloride channel activated by cAMP in the epithelial cell line T84. FEBS Lett 270:157–164
Tabcharani JA, Boucher A, Eng JWL, Hanrahan JW (1994) Regulation of an inwardly rectifying K channel in the Tg4 epithelial cell line by calcium, nucleotides and kinases. J Membr Biol 142:255–266
Tabcharani JA, Chang XB, Riordan JR, Hanrahan JW (1991) Phosphorylation-regulated Cl− channel in CHO cells stably expressing the cystic fibrosis gene. Nature 352:628–631
Wagner ACC, Wishart MJ, Yule DI, Williams JA (1992) Effects of okadaic acid indicate a role for dephosphorylation in pancreatic stimulus-secretion coupling. Am J Physiol 263: C1172-C1180
Warth R, Riedemann N, Bleich M, van Driessche W, Busch AE, Greger R (1996) The cAMP regulated K+ conductance of rat colonic crypt base cells. Pflügers Arch 432:81–88
Welsh MJ (1987) Electrolyte transport by airway epithelia. Physiol Rev 67:1143–1184
Xie J, Drumm ML, Ma J, Davis PB (1995) Intracellular loop between transmembrane segments IV and V of cystic fibrosis transmembrane conductance regulator is involved in regulation of chloride channel conductance state. J Biol Chem 270:28084–28091
Young JA, Cook DI, van Lennep EW, Roberts ML (1987) Secretion by the major salivary glands. In: Johnson L, Christensen J, Jackson M, Jacobson E, Walsh J. (eds) Physiology of the gastrointestinal tract. Raven Press, New York, pp 773–815
Zdebik A, Hug MJ, Greger R (1996) Low concentrations of carbachol induce oscillations of membrane voltage in rat pancreatic acinar cells — no evidence for the activation of non selective cation channels. Cell Physiol Biochem (in press)
Zhao H, Muallem S (1995) Agonist-specific regulation of [Na+]i in pancreatic acinar cells. J Gen Physiol 106:1243–1263
Zhao H, Muallem S (1996) Na+, K+, and Cl− transport in resting pancreatic acinar cells. J Gen Physiol 106:1225–1242
Reddy MM, Quinton PM, Haws C, Wine JJ, Grygorzyk R, Tabcharani JA, Hauraban JW, Gunderson KL, Kopito RR (1996) Failure of the cystic fibrosis transmembrane conductance regulator to conduct ATP. Science 271:1876–1879
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Greger, R. The membrane transporters regulating epithelial NaCl secretion. Pflügers Arch. 432, 579–588 (1996). https://doi.org/10.1007/s004240050173
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DOI: https://doi.org/10.1007/s004240050173