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Airway Epithelial Cell Release of GABA is Regulated by Protein Kinase A

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Abstract

Introduction

γ-amino butyric acid (GABA) is not only the major inhibitory neurotransmitter in the central nervous system (CNS), but it also plays an important role in the lung, mediating airway smooth muscle relaxation and mucus production. As kinases such as protein kinase A (PKA) are known to regulate the release and reuptake of GABA in the CNS by GABA transporters, we hypothesized that β-agonists would affect GABA release from airway epithelial cells through activation of PKA.

Methods

C57/BL6 mice received a pretreatment of a β-agonist or vehicle (PBS), followed by methacholine or PBS. Bronchoalveolar lavage (BAL) was collected and the amount of GABA was quantified using HPLC mass spectrometry. For in vitro studies, cultured BEAS-2B human airway epithelial cells were loaded with 3H-GABA. 3H-GABA released was measured during activation and inhibition of PKA and tyrosine kinase signaling pathways.

Results

β-agonist pretreatment prior to methacholine challenge attenuated in vivo GABA release in mouse BAL and 3H-GABA release from depolarized BEAS-2B cells. GABA release was also decreased in BEAS-2B cells by increases in cAMP but not by Epac or tyrosine kinase activation.

Conclusion

β-agonists decrease GABA release from airway epithelium through the activation of cAMP and PKA. This has important therapeutic implications as β-agonists and GABA are important mediators of both mucus production and airway smooth muscle tone.

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Acknowledgments

We thank Dr. William Gerthoffer, University of South Alabama for sharing cultured human airway smooth muscle cells. This work was supported by the Stony Wold-Herbert Fund (JD, SZ), the National Institutes of Health Grants GM065281, HL122340, and GM008464 (CWE), and The Foundation for Anesthesia Education and Research (FAER) (JD).

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Authors and Affiliations

  1. Department of Anesthesiology, Columbia University, 630 W 168th St., P&S Box 46, New York, NY, 10032, USA

    Jennifer Danielsson, Hiromi Funayama, Peter D. Yim, Dingbang Xu, George Gallos & Charles W. Emala

  2. Department of Pediatrics, Columbia University, New York, NY, 10032, USA

    Sarah Zaidi

  3. Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA

    Benjamin Kim & Tilla S. Worgall

  4. Department of Pediatric Dentistry, Tsurumi University School of Dental Medicine, Yokohama, Japan

    Hiromi Funayama

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  1. Jennifer Danielsson
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Correspondence to Jennifer Danielsson.

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Danielsson, J., Zaidi, S., Kim, B. et al. Airway Epithelial Cell Release of GABA is Regulated by Protein Kinase A. Lung 194, 401–408 (2016). https://doi.org/10.1007/s00408-016-9867-2

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