期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 153, 期 6, 页码 1311-1323出版社
WILEY
DOI: 10.1038/sj.bjp.0707663
关键词
ATP-binding cassette transporter; CFTR; cystic fibrosis; chloride ion channel; protein processing; channel block; genistein; CFTR potentiators; pharmacological chaperones; therapy
Background and purpose: Cystic fibrosis (CF) is caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) CI- channel. In the search for new CF therapies, small molecules have been identified that rescue the defective channel gating of CF mutants (termed CFTR potentiators). Here, we investigate the long-term effects of genistein, the best-studied CFTR potentiator, on the expression and function of CFTR. Experimental approach: We pre-treated baby hamster kidney (BHK) cells expressing wild-type or F508del-CFTR ( the most common CF mutant) with concentrations of genistein that potentiate (30 mu M) or inhibit (100 mu M) CFTR function for 2 or 24 h at 37 degrees C before examining CFTR maturation, expression and single-channel activity. Key results: Using the iodide efflux technique, we found that genistein pre-treatment failed to restore function to F508del-CFTR, but altered that of wild-type CFTR. Pre-treatment of cells with genistein for 2 h had little effect on CFTR processing, whereas pre-treatment for 24 h either augmented (30 mu M genistein) or impaired (100 mu M genistein) CFTR maturation. Using immunocytochemistry, we found that all genistein pre-treatments increased the localization of CFTR protein to the cell surface. However, following the incubation of cells with genistein (100 mu M) for 2 h, individual CFTR CI- channels exhibited characteristics of channel block upon channel activation. Conclusions and implications: Genistein pre-treatment alters the maturation, cell surface expression and single-channel function of CFTR in ways distinct from its acute effects. Thus, CFTR potentiators have the potential to influence CFTR by mechanisms distinct from their effects on channel gating.
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