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 language | English |
|---|---|
| Pages (from-to) | 88-95 |
| Number of pages | 8 |
| Journal | Pflugers Archiv European Journal of Physiology |
| Volume | 449 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2004 Oct |
| Externally published | Yes |
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Keywords
- Chloride channel
- Cystic fibrosis
- Patch clamp
- Single channel
ASJC Scopus subject areas
- Physiology
Cite this
Direct effects of 9-anthracene compounds on cystic fibrosis transmembrane conductance regulator gating. / Ai, Tomohiko; Bompadre, Silvia G.; Sohma, Yoshiro; Wang, Xiaohui; Li, Min; Hwang, Tzyh Chang.
In: Pflugers Archiv European Journal of Physiology, Vol. 449, No. 1, 10.2004, p. 88-95.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Direct effects of 9-anthracene compounds on cystic fibrosis transmembrane conductance regulator gating
AU - Ai, Tomohiko
AU - Bompadre, Silvia G.
AU - Sohma, Yoshiro
AU - Wang, Xiaohui
AU - Li, Min
AU - Hwang, Tzyh Chang
PY - 2004/10
Y1 - 2004/10
N2 - 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.
AB - 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.
KW - Chloride channel
KW - Cystic fibrosis
KW - Patch clamp
KW - Single channel
UR - http://www.scopus.com/inward/record.url?scp=8644275441&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=8644275441&partnerID=8YFLogxK
U2 - 10.1007/s00424-004-1317-y
DO - 10.1007/s00424-004-1317-y
M3 - Article
C2 - 15290302
AN - SCOPUS:8644275441
VL - 449
SP - 88
EP - 95
JO - Pflugers Archiv European Journal of Physiology
JF - Pflugers Archiv European Journal of Physiology
SN - 0031-6768
IS - 1
ER -