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

  • Ion Channels, Transporters
  • Published:
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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 Mg2+-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.

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Acknowledgements

The authors are grateful to Shenghui Hu for his technical assistance. This work was supported by the National Institutes of Health (TCH, DK55835, HL53445). Dr. Ai is a recipient of Postdoctoral Fellowship from the American Heart Association, Heartland Affiliate. Dr. Bompadre is the recipient of a NRSA from the National Institutes of Health (DK062565). Dr. Sohma is the recipient of a grant from the Japan Society for the Promotion of Science (15590196).

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Authors and Affiliations

  1. Department of Medical Pharmacology and Physiology, Dalton Cardiovascular Research Center, University of Missouri-Columbia, MO 65211, USA

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

  2. Department of Physiology, Osaka Medical College, Takatsuki, 569-0081, Osaka, Japan

    Yoshiro Sohma

  3. Cardiac Electrophysiology Research Laboratory, Texas Heart Institute, St Luke’s Episcopal Hospital, Houston, TX 77030, USA

    Tomohiko Ai

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  1. Tomohiko Ai
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  2. Silvia G. Bompadre
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  5. Min Li
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  6. Tzyh-Chang Hwang
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Correspondence to Tzyh-Chang Hwang.

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Ai, T., Bompadre, S.G., Sohma, Y. et al. Direct effects of 9-anthracene compounds on cystic fibrosis transmembrane conductance regulator gating. Pflugers Arch - Eur J Physiol 449, 88–95 (2004). https://doi.org/10.1007/s00424-004-1317-y

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