Skip to main content
Log in

Current insights into the role of PKA phosphorylation in CFTR channel activity and the pharmacological rescue of cystic fibrosis disease-causing mutants

  • Multi-author review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) channel gating is predominantly regulated by protein kinase A (PKA)-dependent phosphorylation. In addition to regulating CFTR channel activity, PKA phosphorylation is also involved in enhancing CFTR trafficking and mediating conformational changes at the interdomain interfaces of the protein. The major cystic fibrosis (CF)-causing mutation is the deletion of phenylalanine at position 508 (F508del); it causes many defects that affect CFTR trafficking, stability, and gating at the cell surface. Due to the multiple roles of PKA phosphorylation, there is growing interest in targeting PKA-dependent signaling for rescuing the trafficking and functional defects of F508del-CFTR. This review will discuss the effects of PKA phosphorylation on wild-type CFTR, the consequences of CF mutations on PKA phosphorylation, and the development of therapies that target PKA-mediated signaling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Billet A et al (2016) Potential sites of CFTR activation by tyrosine kinases. Channels (Austin) 10(3):247–251

    Article  Google Scholar 

  2. Billet A et al (2015) Regulation of the cystic fibrosis transmembrane conductance regulator anion channel by tyrosine phosphorylation. Faseb J 29(9):3945–3953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Billet A, Hanrahan JW (2013) The secret life of CFTR as a calcium-activated chloride channel. J Physiol 591(21):5273–5278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rabeh WM et al (2012) Correction of both NBD1 energetics and domain interface is required to restore DeltaF508 CFTR folding and function. Cell 148(1–2):150–163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Okiyoneda T et al (2013) Mechanism-based corrector combination restores DeltaF508-CFTR folding and function. Nat Chem Biol 9(7):444–454

    Article  CAS  PubMed  Google Scholar 

  6. McDonald RA et al (1995) Basal expression of the cystic fibrosis transmembrane conductance regulator gene is dependent on protein kinase A activity. Proc Natl Acad Sci U S A 92(16):7560–7564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Matthews RP, McKnight GS (1996) Characterization of the cAMP response element of the cystic fibrosis transmembrane conductance regulator gene promoter. J Biol Chem 271(50):31869–31877

    Article  CAS  PubMed  Google Scholar 

  8. Pasyk S et al (2015) The major cystic fibrosis causing mutation exhibits defective propensity for phosphorylation. Proteomics 15(2–3):447–461

    Article  CAS  PubMed  Google Scholar 

  9. Gadsby DC, Nairn AC (1994) Regulation of CFTR channel gating. Trends Biochem Sci 19(11):513–518

    Article  CAS  PubMed  Google Scholar 

  10. Csanady L et al (2005) Preferential phosphorylation of R-domain Serine 768 dampens activation of CFTR channels by PKA. J Gen Physiol 125(2):171–186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cheng SH et al (1991) Phosphorylation of the R domain by cAMP-dependent protein kinase regulates the CFTR chloride channel. Cell 66(5):1027–1036

    Article  CAS  PubMed  Google Scholar 

  12. Chang XB et al (1993) Protein kinase A (PKA) still activates CFTR chloride channel after mutagenesis of all 10 PKA consensus phosphorylation sites. J Biol Chem 268(15):11304–11311

    CAS  PubMed  Google Scholar 

  13. Seibert FS et al (1999) Influence of phosphorylation by protein kinase A on CFTR at the cell surface and endoplasmic reticulum. Biochim Biophys Acta 1461(2):275–283

    Article  CAS  PubMed  Google Scholar 

  14. Wilkinson DJ et al (1997) CFTR activation: additive effects of stimulatory and inhibitory phosphorylation sites in the R domain. Am J Physiol 273(1 Pt 1):L127–L133

    CAS  PubMed  Google Scholar 

  15. Hegedus T et al (2009) Role of individual R domain phosphorylation sites in CFTR regulation by protein kinase A. Biochim Biophys Acta 1788(6):1341–1349

    Article  CAS  PubMed  Google Scholar 

  16. Neville DC et al (1997) Evidence for phosphorylation of serine 753 in CFTR using a novel metal-ion affinity resin and matrix-assisted laser desorption mass spectrometry. Protein Sci 6(11):2436–2445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. McClure M et al (2012) Purification of CFTR for mass spectrometry analysis: identification of palmitoylation and other post-translational modifications. Protein Eng Des Sel 25(1):7–14

    Article  CAS  PubMed  Google Scholar 

  18. Liang X et al (2012) Phosphorylation-dependent 14-3-3 protein interactions regulate CFTR biogenesis. Mol Biol Cell 23(6):996–1009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rennolds J et al (2008) Cystic fibrosis transmembrane conductance regulator trafficking is mediated by the COPI coat in epithelial cells. J Biol Chem 283(2):833–839

    Article  CAS  PubMed  Google Scholar 

  20. Stevers LM et al (2016) Characterization and small-molecule stabilization of the multisite tandem binding between 14-3-3 and the R domain of CFTR. Proc Natl Acad Sci U S A 113(9):E1152–E1161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cantiello HF (1996) Role of the actin cytoskeleton in the regulation of the cystic fibrosis transmembrane conductance regulator. Exp Physiol 81(3):505–514

    Article  CAS  PubMed  Google Scholar 

  22. Louvet-Vallee S (2000) ERM proteins: from cellular architecture to cell signaling. Biol Cell 92(5):305–316

    Article  CAS  PubMed  Google Scholar 

  23. Naren AP et al (2003) A macromolecular complex of beta 2 adrenergic receptor, CFTR, and ezrin/radixin/moesin-binding phosphoprotein 50 is regulated by PKA. Proc Natl Acad Sci U S A 100(1):342–346

    Article  CAS  PubMed  Google Scholar 

  24. Li C et al (2004) Molecular assembly of cystic fibrosis transmembrane conductance regulator in plasma membrane. J Biol Chem 279(23):24673–24684

    Article  CAS  PubMed  Google Scholar 

  25. Moyer BD et al (2000) The PDZ-interacting domain of cystic fibrosis transmembrane conductance regulator is required for functional expression in the apical plasma membrane. J Biol Chem 275(35):27069–27074

    CAS  PubMed  Google Scholar 

  26. Short DB et al (1998) An apical PDZ protein anchors the cystic fibrosis transmembrane conductance regulator to the cytoskeleton. J Biol Chem 273(31):19797–19801

    Article  CAS  PubMed  Google Scholar 

  27. Sun F et al (2000) E3KARP mediates the association of ezrin and protein kinase A with the cystic fibrosis transmembrane conductance regulator in airway cells. J Biol Chem 275(38):29539–29546

    Article  CAS  PubMed  Google Scholar 

  28. Monterisi S et al (2012) CFTR regulation in human airway epithelial cells requires integrity of the actin cytoskeleton and compartmentalized cAMP and PKA activity. J Cell Sci 125(Pt 5):1106–1117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Alshafie W et al (2014) VIP regulates CFTR membrane expression and function in Calu-3 cells by increasing its interaction with NHERF1 and P-ERM in a VPAC1- and PKCepsilon-dependent manner. Am J Physiol Cell Physiol 307(1):C107–C119

    Article  CAS  PubMed  Google Scholar 

  30. Lobo MJ et al (2016) EPAC1 activation by cAMP stabilizes CFTR at the membrane by promoting its interaction with NHERF1. J Cell Sci 129(13):2599–2612

    Article  CAS  PubMed  Google Scholar 

  31. Holleran JP et al (2013) Regulated recycling of mutant CFTR is partially restored by pharmacological treatment. J Cell Sci 126(Pt 12):2692–2703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bear CE et al (1992) Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR). Cell 68(4):809–818

    Article  CAS  PubMed  Google Scholar 

  33. Aleksandrov AA, Cui L, Riordan JR (2009) Relationship between nucleotide binding and ion channel gating in cystic fibrosis transmembrane conductance regulator. J Physiol 587(Pt 12):2875–2886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhou Z et al (2006) The two ATP binding sites of cystic fibrosis transmembrane conductance regulator (CFTR) play distinct roles in gating kinetics and energetics. J Gen Physiol 128(4):413–422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Vergani P et al (2005) CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains. Nature 433(7028):876–880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Aleksandrov AA, Aleksandrov LA, Riordan JR (2007) CFTR (ABCC7) is a hydrolyzable-ligand-gated channel. Pflugers Arch 453(5):693–702

    Article  CAS  PubMed  Google Scholar 

  37. Gadsby DC, Vergani P, Csanady L (2006) The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature 440(7083):477–483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Cheung JC et al (2008) Molecular basis for the ATPase activity of CFTR. Arch Biochem Biophys 476(1):95–100

    Article  CAS  PubMed  Google Scholar 

  39. Scott-Ward TS et al (2007) Chimeric constructs endow the human CFTR Cl- channel with the gating behavior of murine CFTR. Proc Natl Acad Sci U S A 104(41):16365–16370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bompadre SG et al (2007) G551D and G1349D, two CF-associated mutations in the signature sequences of CFTR, exhibit distinct gating defects. J Gen Physiol 129(4):285–298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ramjeesingh M et al (2008) The intact CFTR protein mediates ATPase rather than adenylate kinase activity. Biochem J 412(2):315–321

    Article  CAS  PubMed  Google Scholar 

  42. Stratford FL et al (2007) The Walker B motif of the second nucleotide-binding domain (NBD2) of CFTR plays a key role in ATPase activity by the NBD1-NBD2 heterodimer. Biochem J 401(2):581–586

    Article  CAS  PubMed  Google Scholar 

  43. Kogan I et al (2002) Studies of the molecular basis for cystic fibrosis using purified reconstituted CFTR protein. Methods Mol Med 70:143–157

    CAS  PubMed  Google Scholar 

  44. Kogan I et al (2001) Perturbation of the pore of the cystic fibrosis transmembrane conductance regulator (CFTR) inhibits its atpase activity. J Biol Chem 276(15):11575–11581

    Article  CAS  PubMed  Google Scholar 

  45. Kidd JF et al (2004) A heteromeric complex of the two nucleotide binding domains of cystic fibrosis transmembrane conductance regulator (CFTR) mediates ATPase activity. J Biol Chem 279(40):41664–41669

    Article  CAS  PubMed  Google Scholar 

  46. Dawson RJ, Locher KP (2006) Structure of a bacterial multidrug ABC transporter. Nature 443(7108):180–185

    Article  CAS  PubMed  Google Scholar 

  47. Locher KP (2009) Review. Structure and mechanism of ATP-binding cassette transporters. Philos Trans R Soc Lond B Biol Sci 364(1514):239–245

    Article  CAS  PubMed  Google Scholar 

  48. Serohijos AW et al (2008) Phenylalanine-508 mediates a cytoplasmic-membrane domain contact in the CFTR 3D structure crucial to assembly and channel function. Proc Natl Acad Sci U S A 105(9):3256–3261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Mornon JP, Lehn P, Callebaut I (2008) Atomic model of human cystic fibrosis transmembrane conductance regulator: membrane-spanning domains and coupling interfaces. Cell Mol Life Sci 65(16):2594–2612

    Article  CAS  PubMed  Google Scholar 

  50. Winter MC, Welsh MJ (1997) Stimulation of CFTR activity by its phosphorylated R domain. Nature 389(6648):294–296

    Article  CAS  PubMed  Google Scholar 

  51. Hwang TC, Sheppard DN (2009) Gating of the CFTR Cl- channel by ATP-driven nucleotide-binding domain dimerisation. J Physiol 587(Pt 10):2151–2161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Mihalyi C, Torocsik B, Csanady L (2016) Obligate coupling of CFTR pore opening to tight nucleotide-binding domain dimerization. Elife 5:e18164

    Article  PubMed  PubMed Central  Google Scholar 

  53. Li C, Ramjeesingh M, Bear CE (1996) Purified cystic fibrosis transmembrane conductance regulator (CFTR) does not function as an ATP channel. J Biol Chem 271(20):11623–11626

    Article  CAS  PubMed  Google Scholar 

  54. Szellas T, Nagel G (2003) Apparent affinity of CFTR for ATP is increased by continuous kinase activity. FEBS Lett 535(1–3):141–146

    Article  CAS  PubMed  Google Scholar 

  55. Li C et al (1996) ATPase activity of the cystic fibrosis transmembrane conductance regulator. J Biol Chem 271(45):28463–28468

    Article  CAS  PubMed  Google Scholar 

  56. Zwick M et al (2016) How phosphorylation and ATPase activity regulate anion flux though the cystic fibrosis transmembrane conductance regulator (CFTR). J Biol Chem 291(28):14483–14498

    Article  CAS  PubMed  Google Scholar 

  57. Wang W et al (2010) ATP-independent CFTR channel gating and allosteric modulation by phosphorylation. Proc Natl Acad Sci U S A 107(8):3888–3893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ostedgaard LS, Baldursson O, Welsh MJ (2001) Regulation of the cystic fibrosis transmembrane conductance regulator Cl- channel by its R domain. J Biol Chem 276(11):7689–7692

    Article  CAS  PubMed  Google Scholar 

  59. Baker JM et al (2007) CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices. Nat Struct Mol Biol 14(8):738–745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kanelis V et al (2010) NMR evidence for differential phosphorylation-dependent interactions in WT and DeltaF508 CFTR. EMBO J 29(1):263–277

    Article  CAS  PubMed  Google Scholar 

  61. Hudson RP et al (2012) Conformational changes relevant to channel activity and folding within the first nucleotide binding domain of the cystic fibrosis transmembrane conductance regulator. J Biol Chem 287(34):28480–28494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Dawson JE, Farber PJ, Forman-Kay JD (2013) Allosteric coupling between the intracellular coupling helix 4 and regulatory sites of the first nucleotide-binding domain of CFTR. PLoS One 8(9):e74347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Grimard V et al (2004) 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 279(7):5528–5536

    Article  CAS  PubMed  Google Scholar 

  64. Chappe V et al (2005) Phosphorylation of CFTR by PKA promotes binding of the regulatory domain. EMBO J 24(15):2730–2740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Lewis HA et al (2004) Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator. EMBO J 23(2):282–293

    Article  CAS  PubMed  Google Scholar 

  66. Mense M et al (2006) In vivo phosphorylation of CFTR promotes formation of a nucleotide-binding domain heterodimer. EMBO J 25(20):4728–4739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. He L et al (2008) Multiple membrane-cytoplasmic domain contacts in the cystic fibrosis transmembrane conductance regulator (CFTR) mediate regulation of channel gating. J Biol Chem 283(39):26383–26390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Fu J, Kirk KL (2001) Cysteine substitutions reveal dual functions of the amino-terminal tail in cystic fibrosis transmembrane conductance regulator channel gating. J Biol Chem 276(38):35660–35668

    Article  CAS  PubMed  Google Scholar 

  69. Naren AP et al (1999) CFTR chloride channel regulation by an interdomain interaction. Science 286(5439):544–548

    Article  CAS  PubMed  Google Scholar 

  70. Bertrand CA et al (2009) SLC26A9 is a constitutively active, CFTR-regulated anion conductance in human bronchial epithelia. J Gen Physiol 133(4):421–438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ehrhardt A et al (2016) Channel gating regulation by the cystic fibrosis transmembrane conductance regulator (CFTR) first cytosolic loop. J Biol Chem 291(4):1854–1865

    Article  CAS  PubMed  Google Scholar 

  72. Wang W, Roessler BC, Kirk KL (2014) An electrostatic interaction at the tetrahelix bundle promotes phosphorylation-dependent cystic fibrosis transmembrane conductance regulator (CFTR) channel opening. J Biol Chem 289(44):30364–30378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gregory RJ et al (1991) Maturation and function of cystic fibrosis transmembrane conductance regulator variants bearing mutations in putative nucleotide-binding domains 1 and 2. Mol Cell Biol 11(8):3886–3893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Eckford PD et al (2012) Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner. J Biol Chem 287(44):36639–36649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Pasyk S et al (2009) Direct interaction of a small-molecule modulator with G551D-CFTR, a cystic fibrosis-causing mutation associated with severe disease. Biochem J 418(1):185–190

    Article  CAS  PubMed  Google Scholar 

  76. Ren XQ et al (2004) Function of the ABC signature sequences in the human multidrug resistance protein 1. Mol Pharmacol 65(6):1536–1542

    Article  CAS  PubMed  Google Scholar 

  77. Riordan JR (2005) Assembly of functional CFTR chloride channels. Annu Rev Physiol 67:701–718

    Article  CAS  PubMed  Google Scholar 

  78. Younger JM et al (2004) A foldable CFTR{Delta}F508 biogenic intermediate accumulates upon inhibition of the Hsc70-CHIP E3 ubiquitin ligase. J Cell Biol 167(6):1075–1085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Younger JM et al (2006) Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane conductance regulator. Cell 126(3):571–582

    Article  CAS  PubMed  Google Scholar 

  80. Farinha CM, Amaral MD (2005) Most F508del-CFTR is targeted to degradation at an early folding checkpoint and independently of calnexin. Mol Cell Biol 25(12):5242–5252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Okiyoneda T et al (2004) Delta F508 CFTR pool in the endoplasmic reticulum is increased by calnexin overexpression. Mol Biol Cell 15(2):563–574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Okiyoneda T et al (2010) Peripheral protein quality control removes unfolded CFTR from the plasma membrane. Science 329(5993):805–810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Gentzsch M et al (2004) Endocytic trafficking routes of wild type and DeltaF508 cystic fibrosis transmembrane conductance regulator. Mol Biol Cell 15(6):2684–2696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Loo TW, Bartlett MC, Clarke DM (2008) Processing mutations disrupt interactions between the nucleotide binding and transmembrane domains of P-glycoprotein and the cystic fibrosis transmembrane conductance regulator (CFTR). J Biol Chem 283(42):28190–28197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. He L et al (2013) Correctors of DeltaF508 CFTR restore global conformational maturation without thermally stabilizing the mutant protein. FASEB J 27(2):536–545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Aleksandrov AA et al (2010) Regulatory insertion removal restores maturation, stability and function of DeltaF508 CFTR. J Mol Biol 401(2):194–210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Wang F et al (2000) Deletion of phenylalanine 508 causes attenuated phosphorylation-dependent activation of CFTR chloride channels. J Physiol 524(Pt 3):637–648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Drumm ML et al (1991) Chloride conductance expressed by delta F508 and other mutant CFTRs in Xenopus oocytes. Science 254(5039):1797–1799

    Article  CAS  PubMed  Google Scholar 

  89. Hegedus T et al (2006) F508del CFTR with two altered RXR motifs escapes from ER quality control but its channel activity is thermally sensitive. Biochim Biophys Acta 1758(5):565–572

    Article  CAS  PubMed  Google Scholar 

  90. Kim Chiaw P et al (2009) Functional rescue of DeltaF508-CFTR by peptides designed to mimic sorting motifs. Chem Biol 16(5):520–530

    Article  PubMed  CAS  Google Scholar 

  91. Chang XB et al (1999) Removal of multiple arginine-framed trafficking signals overcomes misprocessing of delta F508 CFTR present in most patients with cystic fibrosis. Mol Cell 4(1):137–142

    Article  CAS  PubMed  Google Scholar 

  92. Favia M et al (2010) Na +/H + exchanger regulatory factor 1 overexpression-dependent increase of cytoskeleton organization is fundamental in the rescue of F508del cystic fibrosis transmembrane conductance regulator in human airway CFBE41o- cells. Mol Biol Cell 21(1):73–86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Denning GM et al (1992) Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive. Nature 358(6389):761–764

    Article  CAS  PubMed  Google Scholar 

  94. Farinha CM et al (2013) Revertants, low temperature, and correctors reveal the mechanism of F508del-CFTR rescue by VX-809 and suggest multiple agents for full correction. Chem Biol 20(7):943–955

    Article  CAS  PubMed  Google Scholar 

  95. Pedemonte N et al (2005) Small-molecule correctors of defective DeltaF508-CFTR cellular processing identified by high-throughput screening. J Clin Invest 115(9):2564–2571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Van Goor F et al (2011) Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci U S A 108(46):18843–18848

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Abbattiscianni AC et al (2016) Correctors of mutant CFTR enhance subcortical cAMP-PKA signaling through modulating ezrin phosphorylation and cytoskeleton organization. J Cell Sci 129(6):1128–1140

    Article  CAS  PubMed  Google Scholar 

  98. Van Goor F et al (2009) Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A 106(44):18825–18830

    Article  PubMed  PubMed Central  Google Scholar 

  99. Jih KY, Hwang TC (2013) Vx-770 potentiates CFTR function by promoting decoupling between the gating cycle and ATP hydrolysis cycle. Proc Natl Acad Sci U S A 110(11):4404–4409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Loureiro CA et al (2015) A molecular switch in the scaffold NHERF1 enables misfolded CFTR to evade the peripheral quality control checkpoint. Sci Signal 8(377):ra48

    Article  PubMed  CAS  Google Scholar 

  101. Turner MJ et al (2016) The dual phosphodiesterase 3 and 4 inhibitor RPL554 stimulates CFTR and ciliary beating in primary cultures of bronchial epithelia. Am J Physiol Lung Cell Mol Physiol 310(1):L59–L70

    Article  PubMed  Google Scholar 

  102. Li C, Naren AP (2011) Analysis of CFTR interactome in the macromolecular complexes. Methods Mol Biol 741:255–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Li C, Naren AP (2010) CFTR chloride channel in the apical compartments: spatiotemporal coupling to its interacting partners. Integr Biol (Camb) 2(4):161–177

    Article  CAS  Google Scholar 

  104. Moon C et al (2015) Compartmentalized accumulation of cAMP near complexes of multidrug resistance protein 4 (MRP4) and cystic fibrosis transmembrane conductance regulator (CFTR) contributes to drug-induced diarrhea. J Biol Chem 290(18):11246–11257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Li C et al (2007) Spatiotemporal coupling of cAMP transporter to CFTR chloride channel function in the gut epithelia. Cell 131(5):940–951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Arora K, Naren AP (2016) Pharmacological correction of cystic fibrosis: molecular mechanisms at the plasma membrane to augment mutant CFTR function. Curr Drug Targets 17(11):1275–1281

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

S. Chin was supported by a NSERC scholarship (PGS-D) and the research activities in the Bear Lab supported in part by the Canadian Institutes of Health Research and Cystic Fibrosis Canada.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Christine E. Bear.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chin, S., Hung, M. & Bear, C.E. Current insights into the role of PKA phosphorylation in CFTR channel activity and the pharmacological rescue of cystic fibrosis disease-causing mutants. Cell. Mol. Life Sci. 74, 57–66 (2017). https://doi.org/10.1007/s00018-016-2388-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-016-2388-6

Keywords

Navigation