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

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.

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 (3)H-GABA. (3)H-GABA released was measured during activation and inhibition of PKA and tyrosine kinase signaling pathways.

β-agonist pretreatment prior to methacholine challenge attenuated in vivo GABA release in mouse BAL and (3)H-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.

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.