British journal of pharmacology · 2026
Agonist-specific conformational dynamics at the β2-adrenoceptor dictate allosteric modulation of Gαs signalling and bronchodilation.
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Shah Sushrut D, Richard Joshua, Ghosh Suvankar, Jerwick Jillian, Gavali Joice T, Penn Raymond B, MacKerell Alexander D, Deshpande Deepak A
Аннотация
BACKGROUND AND PURPOSE: β2-adrenoceptor (β2AR) agonists are the cornerstone of asthma therapy and promote bronchodilation through Gαs signalling in airway smooth muscle (ASM), but their efficacy is limited by β-arrestin-mediated β2AR desensitization. We recently described allosteric modulators (AMs) of β2AR that preferentially enhance isoproterenol-mediated β2AR-Gαs signalling in ASM. Orthosteric β-agonists differ in efficacy, kinetics and signalling bias, and how this diversity shapes allosteric modulation of β2ARs remains unclear. We investigated whether AMs could selectively modulate β2AR-Gαs signalling and bronchodilation in response to endogenous and clinically relevant β-agonists.
EXPERIMENTAL APPROACH: The effects of a positive AM (PAM37) and two negative AMs (NAM36 and NAM42) were examined on β-agonist-induced Gαs and β-arrestin recruitment and downstream signalling (cAMP, PKA and ERK) in HEK293 cells expressing β2ARs and primary human ASM cells. Bronchodilation was assessed using murine precision-cut lung slices and in vivo lung mechanics. Molecular dynamics (MD) simulations were performed to delineate structural determinants of agonist-dependent AM activity.
KEY RESULTS: PAM37 enhanced, whereas NAMs attenuated β2AR-Gαs coupling, signalling and bronchodilation with no effect on β-arrestin-ERK signalling, establishing Gαs signalling and functional bias. AM effects differed in magnitude and kinetic profiles across β-agonists, with fenoterol uniquely resistant to modulation. MD simulations revealed that fenoterol stabilizes a quasi-inactive β2AR conformation characterized by an TM6 shift that occludes the allosteric pocket, providing a structural basis for its resistance.
CONCLUSIONS AND IMPLICATIONS: These findings establish orthosteric ligand-dependent allostery as a fundamental feature of β2AR pharmacology. PAM37 represents a tool to selectively enhance bronchodilation by β-agonists in asthma.
EXPERIMENTAL APPROACH: The effects of a positive AM (PAM37) and two negative AMs (NAM36 and NAM42) were examined on β-agonist-induced Gαs and β-arrestin recruitment and downstream signalling (cAMP, PKA and ERK) in HEK293 cells expressing β2ARs and primary human ASM cells. Bronchodilation was assessed using murine precision-cut lung slices and in vivo lung mechanics. Molecular dynamics (MD) simulations were performed to delineate structural determinants of agonist-dependent AM activity.
KEY RESULTS: PAM37 enhanced, whereas NAMs attenuated β2AR-Gαs coupling, signalling and bronchodilation with no effect on β-arrestin-ERK signalling, establishing Gαs signalling and functional bias. AM effects differed in magnitude and kinetic profiles across β-agonists, with fenoterol uniquely resistant to modulation. MD simulations revealed that fenoterol stabilizes a quasi-inactive β2AR conformation characterized by an TM6 shift that occludes the allosteric pocket, providing a structural basis for its resistance.
CONCLUSIONS AND IMPLICATIONS: These findings establish orthosteric ligand-dependent allostery as a fundamental feature of β2AR pharmacology. PAM37 represents a tool to selectively enhance bronchodilation by β-agonists in asthma.