AutoriFerrera L, Pincin C, Moran O.
AbstractThe human cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the superfamily of adenosine triphosphate (ATP)-binding cassette (ABC) transporter ATPases. This protein forms a Cl(-) channel with a complex regulation; gene mutations cause cystic fibrosis disease. We investigated the interaction between the protein and the flavone UCCF-029 using the patch-clamp technique in the excised inside-out configuration in order to study the molecular mechanism of action for this potentiator on completely phosphorylated channel (25 U/ml protein kinase A) and a relatively low level of ATP (0.3 mM: ). Low concentrations of UCCF-029 (<50 nM: ) increase the open probability (p (o)), favoring the channel transition to an activated state, while high UCCF-029 (>50 nM: ) levels determine inhibition of the CFTR by a reduction of the total open time. Our data suggest that this drug can potentiate CFTR by binding to a specific site on the nucleotide binding domain, promoting dimer formation. The response of CFTR to variable concentrations of ATP is not modified by application of the potentiator UCCF-029 at either low, activatory, concentration or high, inhibitory, levels. Hence, we conclude that the potentiator may not interfere with binding of ATP but probably acts at an independent site in the protein, interacting directly with CFTR to modulate channel activity.
RivistaThe Journal Of Membrane Biology
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Pagina inizio1
Pagina fine9
Autori IBFOscar MORAN
Linee di Ricerca IBFMD.P01.009.001