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Functional Expression of GABA_B Receptors in Airway Epithelium

¹ Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York; and ² Department of Anesthesiology, Gifu University School of Medicine, Gifu, Gifu, Japan

Correspondence and requests for reprints should be addressed to Charles W. Emala, M.D., Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, 630 W. 168th St., P&S Box 46, New York, NY 10032. E-mail: cwe5{at}columbia.edu

-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system and exerts its actions via both ionotropic (GABA_A) and metabotropic (GABA_B) receptors. The GABA_B receptor is a dimer composed of R1 and R2 components and classically couples to the heterotrimeric G_i protein. In addition to their location on neurons, GABA and functional GABA_B receptors have been detected in peripheral tissue such as airway smooth muscle. We questioned whether airway epithelium expresses receptors that could respond to GABA. We detected the mRNA encoding multiple-splice variants of the GABA_BR1 and GABA_BR2 in total RNA isolated from native human and guinea pig airway epithelium and human airway epithelial cell lines (BEAS-2B and H441). Immunoblots identified the GABA_BR1 and GABA_BR2 proteins in both guinea pig airway epithelium and BEAS-2B cells. The expression of GABA_BR1 protein was immunohistochemically localized to basal mucin-secreting and ciliated columnar epithelial cells in guinea pig trachea. Baclofen inhibited adenylyl cyclase activity, induced ERK phosphorylation and cross-regulated phospholipase C, leading to increased inositol phosphates in BEAS-2B cells in a pertussis toxin–sensitive manner, implicating G_i protein coupling. Thus, these receptors couple to G_i and cross-regulate the phospholipase C/inositol phosphate pathway. The second messengers of these pathways, cyclic AMP and calcium, play pivotal roles in airway epithelial cell primary functions of mucus clearance. Furthermore, the enzyme that synthesizes GABA, glutamic acid decarboxylase (GAD65/67), was also localized to airway epithelium. GABA may modulate an uncharacterized signaling cascade via GABA_B receptors coupled to G_i protein in airway epithelium.

Key Words: G protein • adenylyl cyclase • mitogen-activated protein kinase • airway epithelium

CLINICAL RELEVANCE This is a novel demonstration of the functional coupling of the GABAB receptor on airway epithelium to cyclic AMP and calcium signaling pathways, which in turn regulate a fundamental function of airway epithelial cells, mucociliary clearance.