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

Masahiro Morise, Yasushi Ito, Tadakatsu Matsuno, Yoshitaka Hibino, Takefumi Mizutani, Satoru Ito, Naozumi Hashimoto, Masashi Kondo, Kazuyoshi Imaizumi, Yoshinori Hasegawa

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


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 (ISC), after stimulation by forskolin (10μM) 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 ISC 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 HCO3--dependent anion transporters [NBC1/AE2])-sensitive ISC 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.

Original languageEnglish
Pages (from-to)204-211
Number of pages8
JournalEuropean Journal of Pharmacology
Issue number1-3
Publication statusPublished - 06-2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology


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