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1 Children's Hospital Oakland Research Institute, Oakland 94609; and 2 Department of Chemistry, University of California, Davis, California 95616
Apigenin
(4',5,7-trihydroxyflavone) is an activator of cystic fibrosis
transmembrane conductance regulator (CFTR)-mediated Cl
currents across epithelia at low concentrations and a blocker at
high concentrations. We determined the roles of structural components
of apigenin for both stimulation and block of Cl currents
across Calu-3 epithelia. The half-maximal binding affinity of apigenin
for current stimulation (Ks) was 9.1 ± 1.3 µM, and the rank-order of molecular structures was 7-hydroxyl > pyrone = 4'-hydroxyl > 5-hydroxyl. Both the 7-hydroxyl and
the 4'-hydroxyl served as H-bond acceptors, whereas the 5-hydroxyl was
an H-bond donor. The half-maximal binding affinity of apigenin during
current block was 74 ± 11 µM. Blocked Cl currents
were structurally determined by 7-hydroxyl = 4'-hydroxyl > pyrone > 5-hydroxyl. Prestimulation of tissues with forskolin significantly affected activation kinetics and binding characteristics. After forskolin stimulation, Ks was 4.1 ± 0.9 µM, which was structurally determined by pyrone > all
hydroxyls > single hydroxyls. In contrast, block of
Cl current by apigenin was not affected by forskolin
stimulation. We conclude that apigenin binds to a stimulatory and an
inhibitory binding site, which are distinguished by their affinities
and the molecular interactions during binding.
flavonoids; resveratrol; binding site; chloride transport; epithelia; cystic fibrosis transmembrane conductance regulator
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