A quantitative description of the activation and inhibition of CFTR by potentiators: Genistein.
The CFTR, encoded by the gene mutated in cystic fibrosis (CF) patients, is responsible for cAMP dependent chloride transport in epithelia. Substances that activate CFTR have been suggested as possible CF therapy. Most substances investigated so far exert a dual effect on the CFTR: low concentrations stimulate CFTR, whereas higher concentrations inhibit CFTR. Besides, the CFTR phosphorylation level determines the apparent affinity of the drug. We have studied the properties of genistein, the well known CFTR potentiator, by measuring apical membrane current on epithelia formed by cells stably transfected with CFTR and stimulated with different concentrations of CPTcAMP. We propose a quantitative model to describe the activatory and inhibitory effect of genistein, accounting also for the cAMP dependent activation.
Moran
Oscar
O
Instituto di Biofisica, Consiglio Nazionale dela Ricerche, CNR, Via DeMarini, 6, 16149 Genova, Italy. moran@ge.ibf.cnr.it
Zegarra-Moran
Olga
O
D000818:Animals; D002460:Cell Line; D002712:Chlorides / Q000737:chemistry; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology*; D007700:Kinetics; D008956:Models, Chemical; D009711:Nucleotides / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D011916:Rats, Inbred F344; D013961:Thyroid Gland / Q000378:metabolism
D002712:Chlorides; D004791:Enzyme Inhibitors; D009711:Nucleotides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D019833:Genistein; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases