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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 14, 2006; DOI: 10.1124/jpet.106.110718

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Received for publication July 18, 2006.
Revised November 9, 2006.
Accepted for publication November 10, 2006.

Sphingosine 1-phosphate causes airway hyperreactivity by Rho-mediated myosin phosphatase inactivation

Hiroaki Kume 1*, Naoya Takeda 1, Tetsuya Oguma 1, Satoru Ito 1, Masashi Kondo 1, Yasushi Ito 1, Kaoru Shimokata 1

1 Department of Respiratory Medicine, Nagoya University Graduate School of Medicine

* Address correspondence to: E-mail: hkume{at}med.nagoya-u.ac.jp

Abstract

In the present study, we investigated whether extracellular sphingosine 1-phosphate (S1P) is involved in airway hyperreactivity in bronchial asthma. The effects of S1P on the response to methacholine was examined in the fura-2 loaded strips of guinea pig tracheal smooth muscle using simultaneous recording of the isometric tension and the ratio of fluorescence intensities at 340 and 380 nm (F340/F380). A 15-min pretreatment with S1P (>100 nM) markedly enhanced methacholine-induced contraction without elevating F340/F380. This effect of S1P was suppressed in the presence of Y-27632, a selective inhibitor of Rho-kinase, in a concentration-dependent manner. Moreover, pretreatment with pertussis toxin caused an inhibition in S1P-induced hyperreactivity to methacholine in a time- and concentration-dependent manner. In contrast, although S1P-induced Ca2+ mobilization was attenuated by SKF-96365 and verapamil, the subsequent response to methacholine was unaffected. A 15-min pretreatment with lower concentrations of S1P (<100 nM), which is clinically attainable, did not increase methacholine-induced contraction. However, when the incubation was lengthened to 6 h, S1P (<100 nM) enhanced the subsequent response to methacholine. Next, application of S1P to cultured human bronchial smooth muscle cells increased the proportion of active RhoA (GTP-RhoA), and phosphorylation of myosin phosphatase target subunit 1 (MYPT1). This phosphorylation of MYPT1 was significantly inhibited by application of Y-27632, and by pretreatment with pertussis toxin. Our findings demonstrate that exposure of airway smooth muscle to S1P results in airway hyperreactiviy mediated by Ca2+ sensitization via inactivation of myosin phosphatase, which links Gi and RhoA/Rho-kinase processes.


Key words: MYPT1, Rho-kinase, airway hyperresponsiveness, airway smooth muscle, bronchial asthma, lipid mediators


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