A change in gating mode leading to increased intrinsic Cl super(-) channel activity compensates for defective processing in a cystic fibrosis mutant corresponding to a mild form of the disease

The effects of the mild cystic fibrosis (CF) mutation P574H were analysed and compared with those of three severe ones ( Delta I507, Delta F508 and R560T). Immunochemical and functional analyses indicate that the rank order of CFTR expression at the cell surface is: wild type CFTR > P574H >>...

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Bibliographic Details
Published in:The EMBO journal 1995-01, Vol.14 (11), p.2417-2423
Main Authors: Champigny, G, Imler, J-L, Puchelle, E, Dalemans, W, Gribkoff, V, Hinnrasky, J, Dott, K, Barbry, P, Pavirani, A, Lazdunski, M
Format: Article
Language:English
Subjects:
chloride channels
cystic fibrosis
man
transmembrane conductance regulator
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Summary:The effects of the mild cystic fibrosis (CF) mutation P574H were analysed and compared with those of three severe ones ( Delta I507, Delta F508 and R560T). Immunochemical and functional analyses indicate that the rank order of CFTR expression at the cell surface is: wild type CFTR > P574H >> Delta F508 >> R560T similar to 0. Patch-clamp analysis indicates that the open probability of P574H Cl super(-) channels is almost twice as high as that of the wild type CFTR-Cl super(-) channel. This increased intrinsic activity of individual P574H CFTR-Cl super(-) channels compensates for the lower number of P574H CFTR-Cl super(-) channels reaching the cell surface, and probably explains the milder form of CF associated with the P574H mutation. NS004, a recently described activator, restores near normal CFTR activity in cells expressing the P574H-CFTR channel. The P574H mutation modifies the gating mode of the channel with a large increase ( similar to x7) in the mean channel open time. Proline 574 might play an important role in the process connecting ATP hydrolysis at the nucleotide binding domain and opening and closing events of the CFTR-Cl super(-) channel.
ISSN:0261-4189