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Embracing emerging paradigms of G protein-coupled receptor agonism and signaling to address airway smooth muscle pathobiology in asthma

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Abstract

G protein-coupled receptors (GPCRs) regulate numerous airway cell functions, and signaling events transduced by GPCRs are important in both asthma pathogenesis and therapy. Indeed, most asthma therapies target GPCRs either directly or indirectly. Within recent years, our understating of how GPCRs signal and are regulated has changed significantly as new concepts have emerged and traditional ideas have evolved. In this review, we discuss current concepts regarding constitutive GPCR activity and receptor agonism, functional selectivity, compartmentalized signaling, and GPCR desensitization. We further discuss the relevance of these ideas to asthma and asthma therapy, while emphasizing their potential application to the GPCR signaling in airway smooth muscle that regulates airway patency and thus disease severity.

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Notes

  1. Tiotropium is a nonselective mAChR antagonist, but because of its slow off-rate for the m3 mAChR, it preferentially antagonizes m3 mAChR-dependent signaling.

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Acknowledgments

This manuscript was supported by NIH grants HL58506 and AI059755. The author thanks Deepak Deshpande and Anna Misior for help with figure generation and Roland Seifert and Kjetil Tasken for kindly providing permission to reproduce figures.

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  1. Department of Internal Medicine, Wake Forest University Health Sciences Center, Winston-Salem, NC, 27157, USA

    Raymond B. Penn

  2. Center for Human Genomics, Wake Forest University Health Sciences Center, Medical Center Blvd, Winston-Salem, NC, 27157, USA

    Raymond B. Penn

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Penn, R.B. Embracing emerging paradigms of G protein-coupled receptor agonism and signaling to address airway smooth muscle pathobiology in asthma. Naunyn-Schmied Arch Pharmacol 378, 149–169 (2008). https://doi.org/10.1007/s00210-008-0263-1

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