Regulated trafficking of the CFTR chloride channel.
The cystic fibrosis transmembrane conductance regulator (CFTR), the ABC transporter encoded by the cystic fibrosis gene, is localized in the apical membrane of epithelial cells where it functions as a cyclic AMP-regulated chloride channel and as a regulator of other ion channels and transporters. Whereas a key role of cAMP-dependent phosphorylation in CFTR-channel gating has been firmly established, more recent studies have provided clear evidence for the existence of a second level of cAMP regulation, i.e. the exocytotic recruitment of CFFR to the plasma membrane and its endocytotic retrieval. Regulated trafficking of the CFTR Cl- channel has sofar been demonstrated only in a subset of CFTR-expressing cell types. However, with the introduction of more sensitive methods to measure CFTR cycling and submembrane localization, it might turn out to be a more general phenomenon that could contribute importantly to both the regulation of CFTR-mediated chloride transport itself and to the regulation of other transporters and CFTR-modulated cellular functions. This review aims to summarize the present state of knowledge regarding polarized and regulated CFTR trafficking and endosomal recycling in epithelial cells, to discuss present gaps in our understanding of these processes at the cellular and molecular level, and to consider its possible implications for cystic fibrosis.
Kleizen
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Department of Biochemistry, Cardiovascular Research Institute COEUR, Faculty of Medicine and Health Sciences, Erasmus University, Rotterdam, The Netherlands.
Braakman
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de Jonge
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HR
D000818:Animals; D029681:Arabidopsis Proteins; D002352:Carrier Proteins / Q000378:metabolism; D020134:Catalytic Domain / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D000242:Cyclic AMP / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D005089:Exocytosis / Q000502:physiology; D006801:Humans; D026161:MADS Domain Proteins; D008565:Membrane Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010940:Plant Proteins / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology*; D050600:SNARE Proteins; D017923:Sodium-Hydrogen Exchangers; D033921:Vesicular Transport Proteins; D021601:trans-Golgi Network / Q000378:metabolism / Q000648:ultrastructure
D029681:Arabidopsis Proteins; C091536:CAL protein, Arabidopsis; C505032:CFTR protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D026161:MADS Domain Proteins; D008565:Membrane Proteins; C484659:PDZK1 protein, human; D010750:Phosphoproteins; D010940:Plant Proteins; D050600:SNARE Proteins; D017923:Sodium-Hydrogen Exchangers; D033921:Vesicular Transport Proteins; C093376:sodium-hydrogen exchanger regulatory factor; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP