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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; Schr�der, Ralf; Kuschak, Markus; Annala, Suvi; K�nig, Gabriele M.; M�ller, Christa E.; Hall, Ian P.; Kostenis, Evi; Wenzel, Daniela

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


Authors

Michaela Matthey

Alexander Seidinger

Annika Simon

Ralf Schr�der

Markus Kuschak

Suvi Annala

Gabriele M. K�nig

Christa E. M�ller

IAN HALL IAN.HALL@NOTTINGHAM.AC.UK
Professor of Molecular Medicine

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
Acceptance Date Apr 10, 2017
Online Publication Date Sep 13, 2017
Deposit Date Sep 21, 2017
Publicly Available Date Sep 21, 2017
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
DOI https://doi.org/10.1126/scitranslmed.aag2288
Public URL https://nottingham-repository.worktribe.com/output/882345
Publisher URL http://stm.sciencemag.org/content/9/407/eaag2288

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