Allosteric modulator potentiates β2AR agonist–promoted bronchoprotection in asthma models
Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled β2-adrenergic receptor (β2AR) agonists (β2-agonists) promote — with limited efficacy — bronchodilation in asthma. All β2-agonists are canonical orthosteric ligands that bind the same site as endogenous epinep...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2023-09-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI167337 |
| _version_ | 1797634439591755776 |
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| author | Seungkirl Ahn Harm Maarsingh Julia K.L. Walker Samuel Liu Akhil Hegde Hyeje C. Sumajit Alem W. Kahsai Robert J. Lefkowitz |
| author_facet | Seungkirl Ahn Harm Maarsingh Julia K.L. Walker Samuel Liu Akhil Hegde Hyeje C. Sumajit Alem W. Kahsai Robert J. Lefkowitz |
| author_sort | Seungkirl Ahn |
| collection | DOAJ |
| description | Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled β2-adrenergic receptor (β2AR) agonists (β2-agonists) promote — with limited efficacy — bronchodilation in asthma. All β2-agonists are canonical orthosteric ligands that bind the same site as endogenous epinephrine. We recently isolated a β2AR-selective positive allosteric modulator (PAM), compound-6 (Cmpd-6), which binds outside of the orthosteric site and modulates orthosteric ligand functions. With the emerging therapeutic potential of G-protein coupled receptor allosteric ligands, we investigated the impact of Cmpd-6 on β2AR-mediated bronchoprotection. Consistent with our findings using human β2ARs, Cmpd-6 allosterically potentiated β2-agonist binding to guinea pig β2ARs and downstream signaling of β2ARs. In contrast, Cmpd-6 had no such effect on murine β2ARs, which lack a crucial amino acid in the Cmpd-6 allosteric binding site. Importantly, Cmpd-6 enhanced β2 agonist–mediated bronchoprotection against methacholine-induced bronchoconstriction in guinea pig lung slices, but — in line with the binding studies — not in mice. Moreover, Cmpd-6 robustly potentiated β2 agonist–mediated bronchoprotection against allergen-induced airway constriction in lung slices obtained from a guinea pig model of allergic asthma. Cmpd-6 similarly enhanced β2 agonist–mediated bronchoprotection against methacholine-induced bronchoconstriction in human lung slices. Our results highlight the potential of β2AR-selective PAMs in the treatment of airway narrowing in asthma and other obstructive respiratory diseases. |
| first_indexed | 2024-03-11T12:07:46Z |
| format | Article |
| id | doaj.art-7baee4fa0bf4499f85b0ab428028efe2 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:07:46Z |
| publishDate | 2023-09-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-7baee4fa0bf4499f85b0ab428028efe22023-11-07T16:20:51ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-09-0113318Allosteric modulator potentiates β2AR agonist–promoted bronchoprotection in asthma modelsSeungkirl AhnHarm MaarsinghJulia K.L. WalkerSamuel LiuAkhil HegdeHyeje C. SumajitAlem W. KahsaiRobert J. LefkowitzAsthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled β2-adrenergic receptor (β2AR) agonists (β2-agonists) promote — with limited efficacy — bronchodilation in asthma. All β2-agonists are canonical orthosteric ligands that bind the same site as endogenous epinephrine. We recently isolated a β2AR-selective positive allosteric modulator (PAM), compound-6 (Cmpd-6), which binds outside of the orthosteric site and modulates orthosteric ligand functions. With the emerging therapeutic potential of G-protein coupled receptor allosteric ligands, we investigated the impact of Cmpd-6 on β2AR-mediated bronchoprotection. Consistent with our findings using human β2ARs, Cmpd-6 allosterically potentiated β2-agonist binding to guinea pig β2ARs and downstream signaling of β2ARs. In contrast, Cmpd-6 had no such effect on murine β2ARs, which lack a crucial amino acid in the Cmpd-6 allosteric binding site. Importantly, Cmpd-6 enhanced β2 agonist–mediated bronchoprotection against methacholine-induced bronchoconstriction in guinea pig lung slices, but — in line with the binding studies — not in mice. Moreover, Cmpd-6 robustly potentiated β2 agonist–mediated bronchoprotection against allergen-induced airway constriction in lung slices obtained from a guinea pig model of allergic asthma. Cmpd-6 similarly enhanced β2 agonist–mediated bronchoprotection against methacholine-induced bronchoconstriction in human lung slices. Our results highlight the potential of β2AR-selective PAMs in the treatment of airway narrowing in asthma and other obstructive respiratory diseases.https://doi.org/10.1172/JCI167337Therapeutics |
| spellingShingle | Seungkirl Ahn Harm Maarsingh Julia K.L. Walker Samuel Liu Akhil Hegde Hyeje C. Sumajit Alem W. Kahsai Robert J. Lefkowitz Allosteric modulator potentiates β2AR agonist–promoted bronchoprotection in asthma models The Journal of Clinical Investigation Therapeutics |
| title | Allosteric modulator potentiates β2AR agonist–promoted bronchoprotection in asthma models |
| title_full | Allosteric modulator potentiates β2AR agonist–promoted bronchoprotection in asthma models |
| title_fullStr | Allosteric modulator potentiates β2AR agonist–promoted bronchoprotection in asthma models |
| title_full_unstemmed | Allosteric modulator potentiates β2AR agonist–promoted bronchoprotection in asthma models |
| title_short | Allosteric modulator potentiates β2AR agonist–promoted bronchoprotection in asthma models |
| title_sort | allosteric modulator potentiates β2ar agonist promoted bronchoprotection in asthma models |
| topic | Therapeutics |
| url | https://doi.org/10.1172/JCI167337 |
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