Capsaicinoids regulate airway anion transporters through rho kinase- and cyclic AMP-dependent mechanisms

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

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4 Citations (Scopus)

Abstract

To investigate the effects of capsaicinoids on airway anion transporters, we recorded and analyzed transepithelial currents in human airway epithelial Calu-3 cells. Application of capsaicin (100 μM) attenuated vectorial anion transport, estimated as short-circuit currents (I SC), before and after stimulation by forskolin (10 μM) with concomitant reduction of cytosolic cyclic AMP (cAMP) levels. The capsaicin-induced inhibition of I SC was also observed in the response to 8-bromo-cAMP (1 mM, a cell-permeable cAMP analog) and 3-isobutyl-1-methylxanthine (1 mM, an inhibitor of phosphodiesterases). The capsaicin-induced inhibition of I SC was attributed to suppression of bumetanide (an inhibitor of the basolateral Na +-K +-2 Cl -cotransporter 1)- and 4,4′-dinitrostilbene-2,2′-disulfonic acid (an inhibitor of basolateral HCO 3 -2-dependent anion transporters)-sensitive components, which reflect anion uptake via basolateral cAMP-dependent anion transporters. In contrast, capsaicin potentiated apical Cl - conductance, which reflects conductivity through the cystic fibrosis transmembrane conductance regulator, a cAMP-regulated Cl - channel. All these paradoxical effects of capsaicin were mimicked by capsazepine. Forskolin application also increased phosphorylated myosin phosphatase target subunit 1, and the phosphorylation was prevented by capsaicin and capsazepine, suggesting that these capsaicinoids assume aspects of Rho kinase inhibitors. We also found that the increments in apical Cl - conductance were caused by conventional Rho kinase inhibitors, Y-27632 (20 μM) and HA-1077 (20 μM), with selective inhibition of basolateral Na +-K +-2 Cl - cotransporter 1. Collectively, capsaicinoids inhibit cAMP-mediated anion transport through down-regulation of basolateral anion uptake, paradoxically accompanied by upregulation of apical cystic fibrosis transmembrane conductance regulator-mediated anion conductance. The latter is mediated by inhibition of Rho-kinase, which is believed to interact with actin cytoskeleton.

Original languageEnglish
Pages (from-to)684-691
Number of pages8
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume45
Issue number4
DOIs
Publication statusPublished - 01-10-2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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  • Cite this

    Hibino, Y., Morise, M., Ito, Y., Mizutani, T., Matsuno, T., Ito, S., Hashimoto, N., Sato, M., Kondo, M., Imaizumi, K., & Hasegawa, Y. (2011). Capsaicinoids regulate airway anion transporters through rho kinase- and cyclic AMP-dependent mechanisms. American Journal of Respiratory Cell and Molecular Biology, 45(4), 684-691. https://doi.org/10.1165/rcmb.2010-0332OC