Direct effects of 9-anthracene compounds on cystic fibrosis transmembrane conductance regulator gating

Tomohiko Ai, Silvia G. Bompadre, Yoshiro Sohma, Xiaohui Wang, Min Li, Tzyh Chang Hwang

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

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 ΔR-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.

Original languageEnglish (US)
Pages (from-to)88-95
Number of pages8
JournalPflugers Archiv European Journal of Physiology
Volume449
Issue number1
DOIs
StatePublished - Oct 1 2004

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Keywords

  • Chloride channel
  • Cystic fibrosis
  • Patch clamp
  • Single channel

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

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