Interrelationship between the Na+/glucose cotransporter and CFTR in Caco-2 cells: relevance to cystic fibrosis.
Both the Na+-dependent glucose cotransporter (SGLT1) and the cystic fibrosis transmembrane conductance regulator (CFTR) modulate Na+ and fluid movement, although in opposite directions. Yet few studies have investigated a possible interrelationship between these two transporters. By using the Caco-2 human colon carcinoma cell line, we confirmed that the activities of these transporters increased with spontaneous differentiation to the enterocytic phenotype. We showed that SGLT1 was positively regulated by Cl- and that optimal activity of CFTR was dependent on the presence of glucose. We also demonstrated that inhibition of CFTR by glibenclamide or diphenylamine-2-carboxylate did not modify the activity of SGLT1 and inhibition of SGLT1 by phlorizin did not modify the activity of CFTR, although it resulted in inhibition of glycoconjugate synthesis. These results point to positive substrate-cross regulation of SGLT1 and CFTR and suggest that NaCl and glucose are important for not only Na+ absorption and fluid movement, but also for cAMP-dependent Cl- efflux, and glycoconjugate synthesis, functions that are known to be anomalous in cystic fibrosis.
Institut National de la Santé et de la Recherche Médicale U. 402, Faculté de Médecine Saint-Antoine, Paris, France.
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Mailleau
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Capeau
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Brahimi-Horn
D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D018938:Caco-2 Cells / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002712:Chlorides / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D006001:Glycoconjugates / Q000096:biosynthesis; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009004:Monosaccharide Transport Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010695:Phlorhizin / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism / Q000494:pharmacology; D051269:Sodium-Glucose Transporter 1; D013873:Thionucleotides / Q000494:pharmacology; D062367:ortho-Aminobenzoates / Q000037:antagonists & inhibitors
C505032:CFTR protein, human; D002121:Calcium Channel Blockers; D002712:Chlorides; D004791:Enzyme Inhibitors; D006001:Glycoconjugates; D008562:Membrane Glycoproteins; D009004:Monosaccharide Transport Proteins; C495674:SLC5A1 protein, human; D051269:Sodium-Glucose Transporter 1; D013873:Thionucleotides; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D062367:ortho-Aminobenzoates; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; C001209:fenamic acid; D012964:Sodium; D010695:Phlorhizin; D000242:Cyclic AMP; D005947:Glucose; D005905:Glyburide