Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma
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 r...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
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American Association for the Advancement of Science
2017
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| Online Access: | https://eprints.nottingham.ac.uk/46589/ |
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| author | 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 |
| author_facet | 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 |
| author_sort | Matthey, Michaela |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T20:02:40Z |
| format | Article |
| id | nottingham-46589 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T20:02:40Z |
| publishDate | 2017 |
| publisher | American Association for the Advancement of Science |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-465892020-05-04T19:06:06Z https://eprints.nottingham.ac.uk/46589/ 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 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. American Association for the Advancement of Science 2017-09-13 Article PeerReviewed 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 and Wenzel, Daniela (2017) Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma. Science Translational Medicine, 9 (407). ISSN 1946-6242 http://stm.sciencemag.org/content/9/407/eaag2288 doi:10.1126/scitranslmed.aag2288 doi:10.1126/scitranslmed.aag2288 |
| spellingShingle | 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 Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma |
| title | Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma |
| title_full | Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma |
| title_fullStr | Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma |
| title_full_unstemmed | Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma |
| title_short | Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma |
| title_sort | targeted inhibition of gq signaling induces airway relaxation in mouse models of asthma |
| url | https://eprints.nottingham.ac.uk/46589/ https://eprints.nottingham.ac.uk/46589/ https://eprints.nottingham.ac.uk/46589/ |