Published ahead of print on April 10, 2008, doi:10.1165/rcmb.2007-0414OC Am. J. Respir. Cell Mol. Biol., Volume 39, Number 3, September 2008, 296-304 A more recent version of this article appeared on September 1, 2008
Submitted on November 13, 2007 Functional Expression of GABAB Receptors in Airway EpitheliumKentaro Mizuta1,1 Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, NY, USA, 2 Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, NY, USA; Department of Anesthesiology, Gifu University School of Medicine, Gifu, Gifu, Japan * To whom correspondence should be addressed. E-mail: cwe5{at}columbia.edu.
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-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian CNS and exerts its actions via both ionotropic (GABAA) and metabotropic (GABAB) receptors. The GABAB receptor is a dimer composed of R1 and R2 components and classically couples to the heterotrimeric Gi protein. In addition to their location on neurons, GABA and functional GABAB 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 GABABR1 and GABABR2 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 GABABR1 and GABABR2 proteins in both guinea pig airway epithelium and BEAS-2B cells. The expression of GABABR1 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 Gi protein coupling. Thus, these receptors couple to Gi 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 GABAB receptors coupled to Gi protein in airway epithelium.