2. Academic Validation
  3. Prostaglandin D₂ Induces Ca2+ Sensitization of Contraction without Affecting Cytosolic Ca2+ Level in Bronchial Smooth Muscle

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

  • Int J Mol Sci. 2018 Oct 5;19(10):3036. doi: 10.3390/ijms19103036.
Wataru Suto 1,  Yusuke Ando 2,  Takahiro Hirabayashi 3,  Fumiko Takenoya 4,  Seiji Shioda 5,  Junzo Kamei 6 7,  Hiroyasu Sakai 8,  Yoshihiko Chiba 9
Affiliations

Affiliations

  • 1 Department of Physiology and Molecular Sciences, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. d1502@hoshi.ac.jp.
  • 2 Global Research Center for Innovative Life Science, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. p17andoh@hoshi.ac.jp.
  • 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. t-hirabayashi@hoshi.ac.jp.
  • 4 Department of Physiology and Molecular Sciences, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. kuki@hoshi.ac.jp.
  • 5 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. shioda@hoshi.ac.jp.
  • 6 Global Research Center for Innovative Life Science, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. kamei@hoshi.ac.jp.
  • 7 Department of Biomolecular Pharmacology, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. kamei@hoshi.ac.jp.
  • 8 Department of Biomolecular Pharmacology, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. sakai@hoshi.ac.jp.
  • 9 Department of Physiology and Molecular Sciences, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. chiba@hoshi.ac.jp.
PMID: 30301147 DOI: 10.3390/ijms19103036
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.

Keywords

Ca2+ sensitization; DP1 receptor; RhoA; bronchial smooth muscle hyperresponsiveness; prostaglandin D2 (PGD2).

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