The cystic fibrosis transmembrane conductance regulator Cl-channel: a versatile engine for transepithelial ion transport

( views:73, downloads:0 )
Hongyu LI()
Zhiwei CAI()
Jeng-Haur CHEN()
Min JU()
Zhe XU()
Journal Title:
Volume 59, Issue 04, 2007
Key Word:
ATP-binding cassette transporter;cystic fibrosis transmembrane conductance regulator (CFTR);CFTR interacting proteins;CFTR-opathies;cystic fibrosis;chloride ion channel;epithelial ion transport;macromolecular signalling complex;secretory diarrhoea

Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ATP-binding cassette (ABC) transporter superfamily that forms a Cl- channel with complex regulation. CFTR is composed of five domains: two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs) and a unique regulatory domain (RD). The MSDs assemble to form a low conductance (6-10 pS) anion-selective pore with deep intracellular and shallow extracellular vestibules separated by a selectivity filter.The NBDs form a head-to-tail dimer with two ATP-binding sites (termed sites 1 and 2) located at the dimer interface. Anion flow through CFTR is gated by the interaction of ATP with sites 1 and 2 powering cycles of NBD dimer association and dissociation and hence, conformational changes in the MSDs that open and close the channel pore. The RD is an unstructured domain with multiple consensus phosphorylation sites, phosphorylation of which stimulates CFTR function by enhancing the interaction of ATP with the NBDs. Tight spatial and temporal control of CFTR activity is achieved by macromolecular signalling complexes in which scaffolding proteins colocalise CFTR and plasma membrane receptors with protein kinases and phosphatases. Moreover, a macromolecular complex composed of CFTR and metabolic enzymes (a CFTR metabolon) permits CFTR activity to be coupled tightly to metabolic pathways within cells so that CFTR inhibition conserves vital energy stores. CFTR is expressed in epithelial tissues throughout the body, lining ducts and tubes. It functions to control the quantity and composition of epithelial secretions by driving either the absorption or secretion of salt and water. Of note, in the respiratory airways CFTR plays an additional important role in host defence.Malfunction of CFTR disrupts transepithelial ion transport leading to a wide spectrum of human disease.

  • [1]Quinton PM.Chloride impermeability in cystic fibrosis.Nature 1983; 301:421-422.
  • [2]Riordan JR,Rommens JM,Kerem BS,Alon N,Rozmahel R,Grzelczak Z,Zielenski J,Lok S,Plavsic N,Chou JL,Drumm ML,Iannuzzi MC,Collins FS,Tsui LC.Identification of the cystic fibrosis gene:cloning and characterization of complementary DNA.Science 1989; 245:1066-1073.
  • [3]Anderson MP,Gregory RJ,Thompson S,Souza DW,Paul S,Mulligan RC,Smith AE,Welsh MJ.Demonstration that CFTR is a chloride channel by alteration of its anion selectivity.Science 1991; 253:202-205.
  • [4]Holland IB,Cole SPC,Kuchler K,Higgins CF.ABC Proteins:From Bacteria to Man.London:Academic Press,2003.
  • [5]Sheppard DN,Welsh MJ.Structure and function of the cystic fibrosis transmembrane conductance regulator chloride channel.Physiol Rev 1999; 79:S23-S45.
  • [6]Randak C,Welsh MJ.An intrinsic adenylate kinase activity regulates gating of the ABC transporter CFTR.Cell 2003; 115:837-850.
  • [7]Linsdell P.Mechanism of chloride permeation in the cystic fibrosis transmembrane conductance regulator chloride channel.Exp Physiol 2006; 91:123-129.
  • [8]Ostedgaard LS,Baldursson O,Welsh MJ.Regulation of the cystic fibrosis transmembrane conductance regulator Cl-channel by its R domain.J Biol Chem 2001; 276:7689-7692.
  • [9]Rosenberg MF,Kamis AB,Aleksandrov LA,Ford RC,Riordan JR.Purification and crystallization of the cystic fibrosis transmembrane conductance regulator (CFTR).J Biol Chem 2004; 279:39051-39057.
  • [10]Chen JH,Chang XB,Aleksandrov AA,Riordan JR.CFTR is a monomer:biochemical and functional evidence.J Membr Biol 2002; 188:55-71.
  • [11]Zhang ZR,Cui G,Liu X,Song B,Dawson DC,McCarty NA.Determination of the functional unit of the cystic fibrosis transmembrane conductance regulator chloride channel:one polypeptide forms one pore.J Biol Chem 2005; 280:458-468.
  • [12]McCarty NA.Permeation through the CFTR chloride channel.J Exp Biol 2000; 203:1947-1962.
  • [13]Linsdell P,Hanrahan JW.Adenosine triphosphate-dependent asymmetry of anion permeation in the cystic fibrosis transmembrane conductance regulator chloride channel.J Gen Physiol 1998;111:601-614.
  • [14]Cai Z,Scott-Ward TS,Sheppard DN.Voltage-dependent gating of the cystic fibrosis transmembrane conductance regulator Cl-channel.J Gen Physiol 2003; 122:605-620.
  • [15]Gong X,Burbridge SM,Cowley EA,Linsdell P.Molecular determinants of Au(CN)2-binding and permeability within the cystic fibrosis transmembrane conductance regulator Cl-channel pore.J Physiol 2002; 540:39-47.
  • [16]Ge N,Muise CN,Gong X,Linsdell P.Direct comparison of the functional roles played by different transmembrane regions in the cystic fibrosis transmembrane conductance regulator chloride channel pore.J Biol Chem 2004; 279:55283-55289.
  • [17]St Aubin CN,Linsdell P.Positive charges at the intracellular mouth of the pore regulate anion conduction in the CFTR chloride channel.J Gen Physiol 2006; 128:535-545.
  • [18]Liu X,Smith SS,Dawson DC.CFTR:what's it like inside the pore? J Exp Zool 2003; 300A:69-75.
  • [19]Gong X,Linsdell P.Maximization of the rate of chloride conduction in the CFTR channel pore by ion-ion interactions.Arch Biochem Biophys 2004; 426:78-82.
  • [20]Linsdell P,Tabcharani JA,Rommens JM,Hou YX,Chang XB,Tsui LC,Riordan JR,Hanrahan JW.Permeability of wild-type and mutant cystic fibrosis transmembrane conductance regulator chloride channels to polyatomic anions.J Gen Physiol 1997;110:355-364.
  • [21]Linsdell P,Tabcharani JA,Hanrahan JW.Multi-ion mechanism for ion permeation and block in the cystic fibrosis transmembrane conductance regulator chloride channel.J Gen Physiol 1997;110:365-377.
  • [22]Reddy MM,Quinton PM.Control of dynamic CFTR selectivity by glutamate and ATP in epithelial cells.Nature 2003; 423:756-760.
  • [23]Kogan I,Ramjeesingh M,Li C,Kidd JF,Wang Y,Leslie EM,Cole SPC,Bear CE.CFTR directly mediates nucleotideregulated glutathione flux.EMBO J 2003; 22:1981-1989.
  • [24]Shcheynikov N,Kim KH,Kim K,Dorwart MR,Ko SBH,Goto H,Naruse S,Thomas PJ,Muallem S.Dynamic control of cystic fibrosis transmembrane conductance regulator Cl-/HCO3-selectivity by external Cl-.J Biol Chem 2004; 279:21857-21865.
  • [25]Ko SBH,Zeng W,Dorwart MR,Luo X,Kim KH,Millen L,Goto H,Naruse S,Soyombo A,Thomas PJ,Muallem S.Gating of CFTR by the STAS domain of SLC26 transporters.Nat Cell Biol 2004; 6:343-350.
  • [26]Lewis HA,Buchanan SG,Burley SK,Conners K,Dickey M,Dorwart M,Fowler R,Gao X,Guggino WB,Hendrickson WA,Hunt JF,Kearins MC,Lorimer D,Maloney PC,Post KW,Rajashankar KR,Rutter ME,Sauder JM,Shriver S,Thibodeau PH,Thomas PJ,Zhang M,Zhao X,Emtage S.Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator.EMBO J 2004; 23:282-293.
  • [27]Lewis HA,Zhao X,Wang C,Sauder JM,Rooney I,Noland BW,Lorimer D,Kearins MC,Conners K,Condon B,Maloney PC,Guggino WB,Hunt JF,Emtage S.Impact of the △F508 mutation in first nucleotide-binding domain of human cystic fibrosis transmembrane conductance regulator on domain folding and structure.J Biol Chem 2005; 280:1346-1353.
  • [28]Locher KP,Lee AT,Rees DC.The E.coli BtuCD structure:a framework for ABC transporter architecture and mechanism.Science 2002; 296:1091-1098.
  • [29]Kidd JF,Ramjeesingh M,Stratford F,Huan LJ,Bear CE.A heteromeric complex of the two nucleotide binding domains of cystic fibrosis transmembrane conductance regulator (CFTR) mediates ATPase activity.J Biol Chem 2004; 279:41664-41669.
  • [30]Vergani P,Lockless SW,Nairn AC,Gadsby DC.CFTR channel opening by ATP-driven tight dimerization of its nucleotidebinding domains.Nature 2005; 433:876-880.
  • [31]Gadsby DC,Nairn AC.Control of cystic fibrosis transmembrane conductance regulator channel gating by phosphorylation and nucleotide hydrolysis.Physiol Rev 1999; 79:S77-S107.
  • [32]Aleksandrov L,Aleksandrov AA,Chang KB,Riordan JR.The first nucleotide binding domain of cystic fibrosis transmembrane conductance regulator is a site of stable nucleotide interaction,whereas the second is a site of rapid turnover.J Biol Chem 2002;277:15419-15425.
  • [33]Vergani P,Nairn AC,Gadsby DC.On the mechanism of MgATPdependent gating of CFTR Cl-channels.J Gen Physiol 2003; 120:17-36.
  • [34]Bompadre SG,Hwang TC.Cystic fibrosis transmembrane conductance regulator:a chloride channel gated by ATP binding and hydrolysis.Acta Physiol Sin (生理学报) 2007; 59(4):431-442.
  • [35]Li C,Ramjeesingh M,Wang W,Garami E,Hewryk M,Lee D,Rommens JM,Galley K,Bear CE.ATPase activity of the cystic fibrosis transmembrane conductance regulator.J Biol Chem 1996;271:28463-28468.
  • [36]Amaral MD.Processing of CFTR:traversing the cellular mazehow much CFTR needs to go through to avoid cystic fibrosis?Pediatr Pulmonol 2005; 39:479-491.
  • [37]Dalemans W,Barbry P,Champigny G,Jallat S,Dott K,Dreyer D,Crystal RG,Pavirani A,Lecocq JP,Lazdunski M.Altered chloride ion channel kinetics associated with the △F508 cystic fibrosis mutation.Nature 1991; 354:526-528.
  • [38]Reddy MM,Quinton PM.Deactivation of CFTR-Cl conductance by endogenous phosphatases in the native sweat duct.Am J Physiol 1996; 270:C474-C480.
  • [39]Travis SM,Berger HA,Welsh MJ.Protein phosphatase 2C dephosphorylates and inactivates cystic fibrosis transmembrane conductance regulator.Proc Natl Acad Sci USA 1997; 94:11055-11060.
  • [40]Ostedgaard LS,Baldursson O,Vermeer DW,Welsh MJ,Robertson AD.A functional R domain from cystic fibrosis transmembrane conductance regulator is predominantly unstructured in solution.Proc Natl Acad Sci USA 2000; 97:5657-5662.
  • [41]Cheng SH,Rich DP,Marshall J,Gregory RJ,Welsh MJ,Smith AE.Phosphorylation of the R domain by cAMP-dependent protein kinase regulates the CFTR chloride channel.Cell 1991;66:1027-1036.
  • [42]Rich DP,Berger HA,Cheng SH,Travis SM,Saxena M,Smith AE,Welsh MJ.Regulation of the cystic fibrosis transmembrane conductance regulator Cl-channel by negative charge in the R domain.J Biol Chem 1993; 268:20259-20267.
  • [43]Baldursson O,Berger HA,Welsh MJ.Contribution of R domain phosphoserines to the function of CFTR studied in Fischer rat thyroid epithelia.Am J Physiol 2000; 279:L835-L841.
  • [44]Tabcharani JA,Chang XB,Riordan JR,Hanrahan JW.Phosphorylation-regulated Cl-channel in CHO cells stably expressing the cystic fibrosis gene.Nature 1991; 352:628-631.
  • [45]Wilkinson DJ,Strong TV,Mansoura MK,Wood DL,Smith SS,Collins FS,Dawson DC.CFTR activation:additive effects of stimulatory and inhibitory phosphorylation sites in the R domain.Am J Physiol 1997; 273:L127-L133.
  • [46]Baldursson O,Ostedgaard LS,Rokhlina T,Cotten JF,Welsh MJ.Cystic fibrosis transmembrane conductance regulator Cl-channels with R domain deletions and translocations show phosphorylation-dependent and -independent activity.J Biol Chem 2001; 276:1904-1910.
  • [47]Csanády L,Chan KW,Seto-Young D,Kopsco DC,Nairn AC,Gadsby DC.Severed channels probe regulation of gating of cystic fibrosis transmembrane conductance regulator by its cytoplasmic domains.J Gen Physiol 2000; 116:477-500.
  • [48]Winter MC,Welsh MJ.Stimulation of CFTR activity by its phosphorylated R domain.Nature 1997; 389:294-296.
  • [49]Grimard V,Li C,Ramjeesingh M,Bear CE,Goormaghtigh E,Ruysschaert JM.Phosphorylation-induced conformational changes of cystic fibrosis transmembrane conductance regulator monitored by attenuated total reflection-fourier transform IR spectroscopy and fluorescence spectroscopy.J Biol Chem 2004;279:5528-5536.
  • [50]Mense M,Vergani P,White DM,Altberg G,Nairn AC,Gadsby DC.In vivo phosphorylation of CFTR promotes formation of a nucleotide-binding domain heterodimer.EMBO J 2006; 25:4728-4739.
  • [51]Chappe V,Hinkson DA,Howell LD,Evagelidis A,Liao J,Chang X,Riordan JR,Hanrahan JW.Stimulatory and inhibitory protein kinase C consensus sequences regulate the cystic fibrosis transmembrane conductance regulator.Proc Natl Acad Sci USA 2004; 101:390-395.
  • [52]Guggino WB,Stanton BA.New insights into cystic fibrosis:molecular switches that regulate CFTR.Nat Rev Mol Cell Biol 2006; 7:426-436.
  • [53]Short DB,Trotter KW,Reczek D,Kreda SM,Bretscher A,Boucher RC,Stutts MJ,Milgram SL.An apical PDZ protein anchors the cystic fibrosis transmembrane conductance regulator to the cytoskeleton.J Biol Chem 1998; 273:19797-19801.
  • [54]Naren AP,Cobb B,Li C,Roy K,Nelson D,Heda GD,Liao J,Kirk KL,Sorscher EJ,Hanrahan J,Clancy JP.A macromolecular complex of β2 adrenergic receptor,CFTR,and ezrin/radixin/moesin-binding phosphoprotein 50 is regulated by PKA.Proc Natl Acad Sci USA 2003; 100:342-346.
  • [55]Vastiau A,Cao L,Jaspers M,Owsianik G,Janssens V,Cuppens H,Goris J,Nilius B,Cassiman JJ.Interaction of the protein phosphatase 2A with the regulatory domain of the cystic fibrosis transmembrane conductance regulator channel.FEBS Lett 2005; 579:3392-3396.
  • [56]Zhu T,Dahan D,Evagelidis A,Zheng SX,Luo J,Hanrahan JW.Association of cystic fibrosis transmembrane conductance regulator and protein phosphatase 2C.J Biol Chem 1999; 274:29102-29107.
  • [57]Anderson MP,Berger HA,Rich DP,Gregory RJ,Smith AE,Welsh MJ.Nucleoside triphosphates are required to open the CFTR chloride channel.Cell 1991; 67:775-784.
  • [58]Hallows KR,Raghuram V,Kemp BE,Witters LA,Foskett JK.Inhibition of cystic fibrosis transmembrane conductance regulator by novel interaction with the metabolic sensor AMPactivated protein kinase.J Clin Invest 2000; 105:1711-1721.
  • [59]Hallows KR,McCane JE,Kemp BE,Witters LA,Foskett JK.Regulation of channel gating by AMP-activated protein kinase modulates cystic fibrosis transmembrane conductance regulator activity in lung submucosal cells.J Biol Chem 2003; 278:998-1004.
  • [60]Reithmeier RAF.A membrane metabolon linking carbonic anhydrase with chloride/bicarbonate anion exchangers.Blood Cells Mol Dis 2001; 27:85-89.
  • [61]Crawford RM,Trehame KJ,Best OG,Riemen CE,Muimo R,Gruenert DC,Amaud-Dabernat S,Daniel JY,Mehta A.NDPKA (but not NDPK-B) and AMPK α1 (but not AMPK α2) bind the cystic fibrosis transmembrane conductance regulator in epithelial cell membranes.Cell Signal 2006; 18:1595-1603.
  • [62]Meggio F,Pinna LA.One-thousand-and-one substrates of protein kinase CK2? FASEB J 2003; 17:349-368.
  • [63]Crawford RM,Treharne KJ,Arnaud-Dabernat S,Daniel JY,Foretz B,Viollet B,Mehta A.Protein kinase CK2 acts as a signal molecule switching between the NDPK-A/AMPK α1 complex and NDPK-B.FASEB J 2007; 21:88-98.
  • [64]Treharne KJ,Crawford RM,Xu Z,Chen JH,Best OG,Schulte EA,Gruenert DC,Wilson SM,Sheppard DN,Kunzelmann K,Mehta A.Protein kinase CK2,cystic fibrosis transmembrane conductance regulator,and the △F508 mutation:F508 deletion disrupts a kinase-binding site.J Biol Chem 2007; 282:10804-10813.
  • [65]Welsh MJ,Ramsey BW,Accurso F,Cutting GR.Cystic fibrosis.In:The Metabolic and Molecular Basis of Inherited Disease.Scriver CR,Beaudet AL,Sly WS,Valle D.eds.New York:McGraw-Hill Inc.,2001,5121-5188.
  • [66]Hume JR,Duan D,Collier ML,Yamazaki J,Horowitz B.Anion transport in heart.Physiol Rev 2000; 80:31-81.
  • [67]Forstner G,Kopelman H,Durie P,Corey M.Pancreatic and intestinal dysfunction in cystic fibrosis.In:Genetics and Epithelial Cell Dysfunction in Cystic Fibrosis.Riordan JR,Buchwald M.eds.New York:Alan R.Liss,1987,7-17.
  • [68]Novak I,Greger R.Properties of the luminal membrane of isolated perfused rat pancreatic ducts:effect of cyclic AMP and blockers of chloride transport.Pflügers Arch 1988; 411:546-553.
  • [69]Akiba Y,Jung M,Ouk S,Kaunitz JD.A novel small molecule CFTR inhibitor attenuates HCO3-secretion and duodenal ulcer formation in rats.Am J Physiol 2007; 289:G753-G759.
  • [70]Ma T,Thiagarajah JR,Yang H,Sonawane ND,Folli C,Galietta LJV,Verkman AS.Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks chlolera toxin-induced intestinal fluid secretion.J Clin Invest 2002; 110:1651-1658.
  • [71]Sonawane ND,Hu J,Muanprasat C,Verkman AS.Luminally active,nonabsorbable CFTR inhibitors as potential therapy to reduce intestinal fluid loss in cholera.FASEB J 2006; 20:130-132.
  • [72]Reddy MM,Quinton PM.cAMP activation of CF-affected Cl-conductance in both cell membranes of an absorptive epithelium.J Membr Biol 1992; 130:49-62.
  • [73]Reddy MM,Quinton PM.cAMP-independent phosphorylation activation of CFTR by G proteins in native human sweat duct.Am J Physiol 2001; 280:C604-C613.
  • [74]Reddy MM,Quinton PM.Activation of the epithelial Na+ channel (ENaC) requires CFTR Cl-channel function.Nature 1999;402:301-304.
  • [75]Matsui H,Grubb BR,Tarran R,Randell SH,Gatzy JT,Davis CW,Boucher RC.Evidence for periciliary liquid layer depletion,not abnormal ion composition,in the pathogenesis of cystic fibrosis airways disease.Cell 1998; 95:1005-1015.
  • [76]Smith JJ,Travis SM,Greenberg EP,Welsh MJ.Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid.Cell 1996; 85:229-236.
  • [77]Wine JJ.The genesis of cystic fibrosis lung disease.J Clin Invest 1999; 103:309-312.
  • [78]Engelhardt JF,Yankaskas JR,Ernst SA,Yang Y,Marino CR,Boucher RC,Cohn JA,Wilson JM.Submucosal glands are the predominant site of CFTR expression in the human bronchus.Nat Genet 1992; 2:240-248.
  • [79]Wine JJ,Joo NS.Submucosal glands and airway defense.Proc Am Thorac Soc 2004; 1:47-53.
  • [80]Ianowski JP,Choi JY,Wine JJ,Hanrahan JW.Mucus secretion by single tracheal submucosal glands from normal and cystic fibrosis transmembrane conductance regulator knockout mice.J Physiol 2007; 580:301-314.
  • [81]Di A,Brown ME,Deriy LV,Li C,Szeto FL,Chen Y,Huang P,Tong J,Naren AP,Bindokas V,Palfrey HC,Nelson DJ.CFTR regulates phagosome acidification in macrophages and alters bactericidal activity.Nat Cell Biol 2006; 8:933-944.
  • [82]Morales MM,Carroll TP,Moria T,Schwiebert EM,Devuyst O,Wilson PD,Lopes AG,Stanton BA,Dietz HC,Cutting GR,Guggino WB.Both the wild type and a functional isoform of CFTR are expressed in kidney.Am J Physiol 1996; 270:F1038-F1048.
  • [83]Husted RF,Volk KA,Sigmund RD,Stokes JB.Anion secretion by the inner medullary collecting duct:evidence for involvement of the cysticfibrosis transmembrane conductance regulator.J Clin Invest 1995; 95:644-650.
  • [84]Stanton BA.Cystic fibrosis transmembrane conductance regulator (CFTR) and renal function.Wien Klin Wochenschr 1997;109:457-464.
  • [85]Kibble JD,Balloch KJD,Neal AM,Hill C,White S,Robson L,Green R,Taylor CJ.Renal proximal tubule function is preserved in Cftrtm2cam △F508 cystic fibrosis mice.J Physiol 2001; 532:449-457.
  • [86]Wilson PD.Polycystic kidney disease.N Engl J Med 2004; 350:151-164.
  • [87]Li H,Findlay IA,Sheppard DN.The relationship between cell proliferation,Cl-secretion,and renal cyst growth:a study using CFTR inhibitors.Kidney Int 2004; 66:1926-1938.
  • [88]Inagaki N,Gonoi T,Clement Ⅳ JP,Namba N,Inazawa J,Gonzalez G,Aguilar-Bryan L,Seino S,Bryan J.Reconstitution of IKATP:an inward rectifier subunit plus the sulfonylurea receptor.Science 1995; 270:1166-1170.
  • [89]Scheinman SJ,Guay-Woodford LM,Thakker RV,Warnock DG.Genetic disorders of renal electrolyte transport.N Engl J Med 1999; 340:1177-1187.
  • [90]Beesley AH,Qureshi IZ,Giesberts AN,Parker AJ,White SJ.Expression of the sulphonylurea receptor protein in mouse kidney.Pflügers Arch 1999; 438:1-7.
  • [91]Ruknudin A,Schulze DH,Sullivan SK,Lederer WJ,Welling PA.Novel subunit composition of a renal epithelial KATP channel.J Biol Chem 1998; 273:14165-14171.
  • [92]Lu M,Leng Q,Egan ME,Caplan MJ,Boulpaep EL,Giebisch GH,Hebert SC.CFTR is required for PKA-regulated ATP sensitivity of Kir1.1 potassium channels in mouse kidney.J Clin Invest 2006; 116:797-807.
  • [93]Jouret F,Bernard A,Hermans C,Dom G,Terryn S,Leal T,Lebecque P,Cassiman JJ,Scholte BJ,de Jonge HR,Courtoy PJ,Devuyst O.Cystic fibrosis is associated with a defect in apical receptor-mediated endocytosis in mouse and human kidney.J Am Soc Nephrol 2007; 18:707-718.
  • [94]Chen JH,Cai Z,Li H,Sheppard DN.Function of CFTR protein:ion transport.In:Cystic Fibrosis in the 21st Century.Bush A,Alton EWFW,Davies JC,Griesenbach U,Jaffe A.eds.Basel:Karger,2006,38-44.
  • [95]Cai Z,Chen JH,Hughes LK,Li H,Sheppard DN.The physiology and pharmacology of the CFTR Cl-channel.In:Chloride Movements Across Cellular Membranes.Pusch M.ed.San Diego:Elsevier Limited,2007,109-143.
  • [96]Cai Z,Sheppard DN.Phloxine B interacts with the cystic fibrosis transmembrane conductance regulator at multiple sites to modulate channel activity.J Biol Chem 2002; 277:19546-19553.
  • [97]Cai Z,Taddei A,Sheppard DN.Differential sensitivity of the cystic fibrosis (CF)-associated mutants G551D and G1349D to potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl-channel.J Biol Chem 2006; 281:1970-1977.98 Schutte BC,McCray PB Jr.β-defensins in lung host defense.Annu Rev Physiol 2002; 64:709-748.
  • [97]Cai Z,Taddei A,Sheppard DN.Differential sensitivity of the cystic fibrosis (CF)-associated mutants G551D and G1349D to potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl-channel.J Biol Chem 2006; 281:1970-1977.98 Schutte BC,McCray PB Jr.β-defensins in lung host defense.Annu Rev Physiol 2002; 64:709-748.
  • [98]Schutte BC,McCray PB Jr.β-defensins in lung host defense.Annu Rev Physiol 2002; 64:709-748.
WanfangData CO.,Ltd All Rights Reserved
About WanfangData | Contact US
Healthcare Department, Fuxing Road NO.15, Haidian District Beijing, 100038 P.R.China
Tel:+86-010-58882616 Fax:+86-010-58882615