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Article

Involvement of Ca2+ Signaling in the Synergistic Effects between Muscarinic Receptor Antagonists and β2-Adrenoceptor Agonists in Airway Smooth Muscle

1
Division of Respiratory Medicine, Department of Internal Medicine, Shiga University of Medical Science, Seta, Tsukinowa-cho, Otsu, Shiga 520-2192, Japan
2
Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: Kathleen Van Craenenbroeck
Int. J. Mol. Sci. 2016, 17(9), 1590; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17091590
Received: 1 August 2016 / Revised: 2 September 2016 / Accepted: 8 September 2016 / Published: 21 September 2016
(This article belongs to the Collection G Protein-Coupled Receptor Signaling and Regulation)
Long-acting muscarinic antagonists (LAMAs) and short-acting β2-adrenoceptor agonists (SABAs) play important roles in remedy for COPD. To propel a translational research for development of bronchodilator therapy, synergistic effects between SABAs with LAMAs were examined focused on Ca2+ signaling using simultaneous records of isometric tension and F340/F380 in fura-2-loaded tracheal smooth muscle. Glycopyrronium (3 nM), a LAMA, modestly reduced methacholine (1 μM)-induced contraction. When procaterol, salbutamol and SABAs were applied in the presence of glycopyrronium, relaxant effects of these SABAs are markedly enhanced, and percent inhibition of tension was much greater than the sum of those for each agent and those expected from the BI theory. In contrast, percent inhibition of F340/F380 was not greater than those values. Bisindolylmaleimide, an inhibitor of protein kinase C (PKC), significantly increased the relaxant effect of LAMA without reducing F340/F380. Iberiotoxin, an inhibitor of large-conductance Ca2+-activated K+ (KCa) channels, significantly suppressed the effects of these combined agents with reducing F340/F380. In conclusion, combination of SABAs with LAMAs synergistically enhances inhibition of muscarinic contraction via decreasing both Ca2+ sensitization mediated by PKC and Ca2+ dynamics mediated by KCa channels. PKC and KCa channels may be molecular targets for cross talk between β2-adrenoceptors and muscarinic receptors. View Full-Text
Keywords: cross talk; Ca2+ dynamics; Ca2+ sensitization; large-conductance Ca2+-activated K+ channel; protein kinase C; tracheal smooth muscle; tiotropium; procaterol; COPD cross talk; Ca2+ dynamics; Ca2+ sensitization; large-conductance Ca2+-activated K+ channel; protein kinase C; tracheal smooth muscle; tiotropium; procaterol; COPD
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MDPI and ACS Style

Fukunaga, K.; Kume, H.; Oguma, T.; Shigemori, W.; Tohda, Y.; Ogawa, E.; Nakano, Y. Involvement of Ca2+ Signaling in the Synergistic Effects between Muscarinic Receptor Antagonists and β2-Adrenoceptor Agonists in Airway Smooth Muscle. Int. J. Mol. Sci. 2016, 17, 1590. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17091590

AMA Style

Fukunaga K, Kume H, Oguma T, Shigemori W, Tohda Y, Ogawa E, Nakano Y. Involvement of Ca2+ Signaling in the Synergistic Effects between Muscarinic Receptor Antagonists and β2-Adrenoceptor Agonists in Airway Smooth Muscle. International Journal of Molecular Sciences. 2016; 17(9):1590. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17091590

Chicago/Turabian Style

Fukunaga, Kentaro, Hiroaki Kume, Tetsuya Oguma, Wataru Shigemori, Yuji Tohda, Emiko Ogawa, and Yasutaka Nakano. 2016. "Involvement of Ca2+ Signaling in the Synergistic Effects between Muscarinic Receptor Antagonists and β2-Adrenoceptor Agonists in Airway Smooth Muscle" International Journal of Molecular Sciences 17, no. 9: 1590. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17091590

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