Asthma is a chronic inflammatory disease of the airways whose global prevalence has taken on pandemic proportions. Although research has made great strides in elucidating the underlying mechanisms involved in asthma, in recent decades relatively few new additions have been made to the pharmacological armamentarium for this disease. Our laboratory has made several novel discoveries: (1) that 3-aminobutyric acid subtype A (GABAA) GABAA receptors are expressed on airway smooth muscle cells, (2) that an endogenous GABAergic ligand-receptor system exists in the airway, (3) that activation of endogenous airway smooth muscle GABAA receptors potentiates relaxation, (4) that GABA (endogenously present in the airway) functions to modulate airway smooth muscle tone, (5) that systemic administration of a GABAA receptor agonist administered in vivo attenuates agonist-induced airway constriction and that (6) part of propofol's broncho-relaxant effect is mediated by GABAA receptors on airway smooth muscle. Since pharmacologic specificity of ligands/agonists directed at the GABAA receptor is dictated by GABAA subunit composition, selective targeting of certain subunits restricted to a given tissue hold promise for improved therapy. Therefore, our goal is to elucidate the importance of airway smooth muscle GABAA receptor subunit composition on the modulation of airway smooth muscle tone. We previously demonstrated that human airway smooth muscle expresses a limited, yet highly conserved repertoire of GABAA receptor subunits (including 14, 15, 23, 32 and 42. This limited repertoire of subunits is advantageous, as it may allow for highly selective targeting of GABAA ) receptors expressed on airway smooth muscle. Exciting preliminary data generated for this proposal support the central hypothesis that airway epithelium is an important cellular source for airway GABA. It is released from epithelial cells via kinase- regulated GABA transporters (GAT2 and GAT4/BGT-1) to act upon 14- and/or 15 containing GABAA receptors on airway smooth muscle cells to facilitate relaxation. These findings offer a radical new therapy, a translational therapeutic approach and a novel paradigm for paracrine interactions between airway epithelium and smooth muscle for relaxing airway constriction.

Public Health Relevance

The central hypotheses to be addressed by the studies are that airway epithelium is a cellular source for airway GABA that is released from epithelial cells via kinase-regulated GABA transporters (GAT2 and GAT4/BGT-1). This released GABA can then act upon 14- and/or 15 containing GABAA receptors on airway smooth muscle cells to facilitate relaxation. We plan to identify novel 14 or 15 subunit-selective agonists that can be delivered to airways by aerosol to facilitate airway relaxation. These findings offer a radical new therapy, a translational therapeutic approach and a novel paradigm for paracrine interactions between airway epithelium and smooth muscle for relaxing airway constriction.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM065281-12
Application #
8668987
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2003-04-01
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
Mikami, Maya; Zhang, Yi; Kim, Benjamin et al. (2017) Dexmedetomidine's inhibitory effects on acetylcholine release from cholinergic nerves in guinea pig trachea: a mechanism that accounts for its clinical benefit during airway irritation. BMC Anesthesiol 17:52
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Mikami, Maya; Zhang, Yi; Danielsson, Jennifer et al. (2017) Impaired Relaxation of Airway Smooth Muscle in Mice Lacking the Actin-Binding Protein Gelsolin. Am J Respir Cell Mol Biol 56:628-636
Brown, Amy; Danielsson, Jennifer; Townsend, Elizabeth A et al. (2016) Attenuation of airway smooth muscle contractility via flavonol-mediated inhibition of phospholipase-C?. Am J Physiol Lung Cell Mol Physiol 310:L747-58
Yocum, Gene T; Gallos, George; Zhang, Yi et al. (2016) Targeting the ?-Aminobutyric Acid A Receptor ?4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction. Am J Respir Cell Mol Biol 54:546-53
Danielsson, Jennifer; Zaidi, Sarah; Kim, Benjamin et al. (2016) Airway Epithelial Cell Release of GABA is Regulated by Protein Kinase A. Lung 194:401-8
Forkuo, Gloria S; Guthrie, Margaret L; Yuan, Nina Y et al. (2016) Development of GABAA Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments. Mol Pharm 13:2026-38

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