Direct effects of 9-anthracene compounds on cystic fibrosis transmembrane conductance regulator gating.
Anthracene-9-carboxylic acid (9-AC) has been reported to show both potentiation and inhibitory effects on guinea-pig cardiac cAMP-activated chloride channels via two different binding sites, and inhibition of Mg(2+)-sensitive protein phosphatases has been proposed for the mechanism of 9-AC potentiation effect. In this study, we examined the effects of 9-AC on wild-type and mutant human cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels expressed in NIH3T3 or CHO cells. 9-AC inhibits whole-cell CFTR current in a voltage-dependent manner, whereas the potentiation effect is not affected by membrane potentials. Anthracene-9-methanol, an electro-neutral 9-AC analog, fails to block CFTR, but shows a nearly identical potentiation effect, corroborating the idea that two chemically distinct sites are responsible, respectively, for potentiation and inhibitory actions of 9-AC. 9-AC also enhances the activity of deltaR-CFTR, a constitutively active CFTR mutant whose R-domain is removed. In excised inside-out patches, 9-AC increases Po by prolonging the mean burst durations and shortening the interburst durations. We therefore conclude that two different 9-AC binding sites for potentiation and inhibitory effects on CFTR channels are located outside of the R-domain. We also speculate that 9-AC potentiates CFTR activity by directly affecting CFTR gating.
Department of Medical Pharmacology and Physiology, Dalton Cardiovascular Research Center, University of Missouri-Columbia, MO 65211, USA.
Tomohiko
T
Ai
Silvia G
SG
Bompadre
Yoshiro
Y
Sohma
Xiaohui
X
Wang
Min
M
Li
Tzyh-Chang
TC
Hwang
D000818:Animals; D000873:Anthracenes / Q000378:metabolism* / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D006168:Guinea Pigs; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D051379:Mice; D041681:NIH 3T3 Cells; D018408:Patch-Clamp Techniques
D000873:Anthracenes; C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C010030:9-anthroic acid