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Vol. 296, Issue 2, 464-472, February 2001
Department of Physiology, Dalton Cardiovascular Research
Center, University of Missouri, Columbia, Missouri
We have investigated the mechanism of action of two benzimidazolone
analogs (NS004 and NS1619) on 
F508-CFTR using both whole-cell and
cell-attached patch-clamp techniques and compared their effects with
those of genistein. We conclude that benzimidazolone analogs and
genistein act through a common mechanism, based on the following evidence: 1) both act only on phosphorylated CFTR, 2) the maximal F508-CFTR current activated by benzimidazolone analogs is identical to that induced by genistein, 3) benzimidazolone analogs increase the
open probability of the forskolin-dependent F508-CFTR channel activity through an increase of the channel open time and a decrease of
the channel closed time (effects indistinct from those reported for
genistein), and 4) the prolonged K1250A-CFTR channel open time (in the
presence of 10 µM forskolin) is unaffected by benzimidazolone analogs
or genistein, supporting the hypothesis that these compounds stabilize
the open state by inhibiting ATP hydrolysis at nucleotide binding
domain 2 (NBD2). In addition, we demonstrate that NS004 and NS1619 are
more potent CFTR activators than genistein (EC50 values are
87 ± 14 nM, 472 ± 88 nM, and 4.4 ± 0.5 µM,
respectively). From our studies with the double mutant
F508/K1250A-CFTR, we conclude that benzimidazolone analogs and
genistein rectify the F508-CFTR prolonged closed time independent of
their effects on channel open time, since these agonists enhance
F508/K1250A-CFTR activity by shortening the channel closed time.
These studies should pave the way toward understanding the agonist
binding sites at a molecular level.
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