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Prostaglandin D2 Induces Ca2+ Sensitization of Contraction without Affecting Cytosolic Ca2+ Level in Bronchial Smooth Muscle

1
Department of Physiology and Molecular Sciences, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
2
Global Research Center for Innovative Life Science, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
3
Peptide Drug Innovation Global Research Center for Innovative Life Science, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
4
Department of Biomolecular Pharmacology, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(10), 3036; https://doi.org/10.3390/ijms19103036
Received: 10 September 2018 / Revised: 2 October 2018 / Accepted: 3 October 2018 / Published: 5 October 2018
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Abstract

Prostaglandin D2 (PGD2) is one of the key lipid mediators of allergic airway inflammation, including bronchial asthma. However, the role of PGD2 in the pathogenesis of asthma is not fully understood. In the present study, the effect of PGD2 on smooth muscle contractility of the airways was determined to elucidate its role in the development of airway hyperresponsiveness (AHR). In isolated bronchial smooth muscles (BSMs) of naive mice, application of PGD2 (10−9–10−5 M) had no effect on the baseline tension. However, when the tissues were precontracted partially with 30 mM K+ (in the presence of 10−6 M atropine), PGD2 markedly augmented the contraction induced by the high K+ depolarization. The PGD2-induced augmentation of contraction was significantly inhibited both by 10−6 M laropiprant (a selective DP1 antagonist) and 10−7 M Y-27632 (a Rho-kinase inhibitor), indicating that a DP1 receptor-mediated activation of Rho-kinase is involved in the PGD2-induced BSM hyperresponsiveness. Indeed, the GTP-RhoA pull-down assay revealed an increase in active form of RhoA in the PGD2-treated mouse BSMs. On the other hand, in the high K+-depolarized cultured human BSM cells, PGD2 caused no further increase in cytosolic Ca2+ concentration. These findings suggest that PGD2 causes RhoA/Rho-kinase-mediated Ca2+ sensitization of BSM contraction to augment its contractility. Increased PGD2 level in the airways might be a cause of the AHR in asthma. View Full-Text
Keywords: bronchial smooth muscle hyperresponsiveness; prostaglandin D2 (PGD2); DP1 receptor; Ca2+ sensitization; RhoA bronchial smooth muscle hyperresponsiveness; prostaglandin D2 (PGD2); DP1 receptor; Ca2+ sensitization; RhoA
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Suto, W.; Ando, Y.; Hirabayashi, T.; Takenoya, F.; Shioda, S.; Kamei, J.; Sakai, H.; Chiba, Y. Prostaglandin D2 Induces Ca2+ Sensitization of Contraction without Affecting Cytosolic Ca2+ Level in Bronchial Smooth Muscle. Int. J. Mol. Sci. 2018, 19, 3036.

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