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Heterologous regulation of anion transporters by menthol in human airway epithelial cells.

Abstract：

:The present study concerns previously unreported effects of menthol, a cyclic terpene alcohol produced by the peppermint herb, on anion transporters in polarized human airway Calu-3 epithelia. Application of menthol (0.01-1mM) attenuated transepithelial anion transport, estimated as short-circuit currents (I(SC)), after stimulation by forskolin (10microM) but not before. In contrast, menthol potentiated forskolin-stimulated and -unstimulated apical Cl(-) conductance, which reflected the cystic fibrosis transmembrane conductance regulator (CFTR: the cAMP-regulated Cl(-) channel)-mediated conductance, without correlation to changes in cytosolic cAMP levels. These results indicate that menthol-induced attenuation of forskolin-induced I(SC) despite CFTR up-regulation was due to cAMP-independent inhibition of basolateral anion uptake, which is the rate-limiting step for transepithelial anion transport. Analyses of the responsible basolateral anion transporters revealed that forskolin increased both bumetanide (an inhibitor of the basolateral Na(+)-K(+)-2Cl(-) cotransporter [NKCC1])- and DNDS (an inhibitor of basolateral HCO(3)(-)-dependent anion transporters [NBC1/AE2])-sensitive I(SC) in the control whereas only the former was prevented by the application of menthol. Neither the bumetanide- nor DNDS-sensitive component was, however, reduced by menthol without forskolin. These heterologous effects of menthol were reproduced by latrunculin B, an inhibitor of actin polymerization. F-actin staining showed that menthol prevented forskolin-stimulated rearrangements of actin microfilaments without affecting the distribution of forskolin-unstimulated microfilaments. Collectively, menthol functions as an activator of CFTR and prevents activation of NKCC1 without affecting NBC1/AE although all of these transporters are commonly cAMP-dependent. The heterologous effects may be mediated by the actin cytoskeleton, which interacts with CFTR and NKCC1.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Morise M,Ito Y,Matsuno T,Hibino Y,Mizutani T,Ito S,Hashimoto N,Kondo M,Imaizumi K,Hasegawa Y

doi

10.1016/j.ejphar.2010.03.032

subject

Has Abstract

pub_date

2010-06-10 00:00:00

pages

204-11

issue

1-3

eissn

0014-2999

issn

1879-0712

pii

S0014-2999(10)00229-3

journal_volume

635

pub_type

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Heterologous regulation of anion transporters by menthol in human airway epithelial cells.