Model of the cAMP activation of chloride transport by CFTR channel and the mechanism of potentiators.
Mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis, a hereditary lethal disease. CFTR is a chloride channel expressed in the apical membrane of epithelia. It is activated by cAMP dependent phosphorylation and gated by the binding of ATP. The impaired chloride transport of some types of cystic fibrosis mutations could be pharmacologically solved by the use of chemical compounds called potentiators. Here it is undertaken the construction of a model of the CFTR activation pathways, and the possible modification produced by a potentiator application. The model yields a novel mechanism for the potentiator action, describing the activatory and inhibitory activities on two different positions in the CFTR activation pathway.
Moran
Oscar
O
Istituto di Biofisica, Genova, Italy. moran@ge.ibf.cnr.it
D000255:Adenosine Triphosphate / Q000378:metabolism; D020134:Catalytic Domain; D002712:Chlorides / Q000378:metabolism*; D003198:Computer Simulation; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D008954:Models, Biological; D010766:Phosphorylation / Q000502:physiology; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases