| Autor: |
Lansdell, K. A., Cai, Z., Kidd, J. F., Sheppard, D. N. |
| Zdroj: |
Journal of Physiology; April 2000, Vol. 524 Issue: 2 p317-330, 14p |
| Abstrakt: |
1The isoflavone genistein may either stimulate or inhibit cystic fibrosis transmembrane conductance regulator (CFTR) Cl−channels. To investigate how genistein inhibits CFTR, we studied CFTR Cl−channels in excised inside‐out membrane patches from cells expressing wild‐type human CFTR.2Addition of genistein (100 μM) to the intracellular solution caused a small decrease in single‐channel current amplitude (i),but a large reduction in open probability (Po).3Single‐channel analysis of channel block suggested that genistein (100 μM) may inhibit CFTR by two mechanisms: first, it may slow the rate of channel opening and second, it may block open channels.4Acidification of the intracellular solution relieved channel block, suggesting that the anionic form of genistein may inhibit CFTR.5Genistein inhibition of CFTR Cl−currents was weakly voltage dependent and unaffected by changes in the extracellular Cl−concentration.6Channel block was relieved by pyrophosphate (5 mM) and ATP (5 mM), two agents that interact with the nucleotide‐binding domains (NBDs) of CFTR to greatly stimulate channel activity.7ATP (5 mM) prevented the genistein‐induced decrease in Po, but was without effect on the genistein‐induced decrease in i.8The genistein‐induced decrease in iwas voltage dependent, whereas the genistein‐induced decrease in Powas voltage independent.9The data suggest that genistein may inhibit CFTR by two mechanisms. First, it may interact with NBD1 to potently inhibit channel opening. Second, it may bind within the CFTR pore to weakly block Cl−permeation. |
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