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Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma

Matthey, Michaela; Roberts, Richard; Seidinger, Alexander; Simon, Annika; Schröder, Ralf; Kuschak, Markus; Annala, Suvi; König, Gabriele M.; Müller, Christa E.; Hall, Ian P.; Kostenis, Evi; Wenzel, Daniela

Authors

Michaela Matthey

Richard Roberts

Alexander Seidinger

Annika Simon

Ralf Schröder

Markus Kuschak

Suvi Annala

Gabriele M. König

Christa E. Müller

Ian P. Hall

Evi Kostenis

Daniela Wenzel



Abstract

Obstructive lung diseases are common causes of disability and death worldwide. A hallmark feature is aberrant activation of Gq protein–dependent signaling cascades. Currently, drugs targeting single G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptors (GPCRs) are used to reduce airway tone. However, therapeutic efficacy is often limited, because various GPCRs contribute to bronchoconstriction, and chronic exposure to receptor-activating medications results in desensitization. We therefore hypothesized that pharmacological Gq inhibition could serve as a central mechanism to achieve efficient therapeutic bronchorelaxation. We found that the compound FR900359 (FR), a membrane-permeable inhibitor of Gq, was effective in silencing Gq signaling in murine and human airway smooth muscle cells. Moreover, FR both prevented bronchoconstrictor responses and triggered sustained airway relaxation in mouse, pig, and human airway tissue ex vivo. Inhalation of FR in healthy wild-type mice resulted in high local concentrations of the compound in the lungs and prevented airway constriction without acute effects on blood pressure and heart rate. FR administration also protected against airway hyperreactivity in murine models of allergen sensitization using ovalbumin and house dust mite as allergens. Our findings establish FR as a selective Gq inhibitor when applied locally to the airways of mice in vivo and suggest that pharmacological blockade of Gq proteins may be a useful therapeutic strategy to achieve bronchorelaxation in asthmatic lung disease.

Journal Article Type Article
Journal Science Translational Medicine
Print ISSN 1946-6234
Electronic ISSN 1946-6242
Publisher American Association for the Advancement of Science
Peer Reviewed Peer Reviewed
Volume 9
Issue 407
APA6 Citation Matthey, M., Roberts, R., Seidinger, A., Simon, A., Schröder, R., Kuschak, M., …Wenzel, D. (in press). Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma. Science Translational Medicine, 9(407), doi:10.1126/scitranslmed.aag2288
DOI https://doi.org/10.1126/scitranslmed.aag2288
Publisher URL http://stm.sciencemag.org/content/9/407/eaag2288
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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