title: Selective targeting of the α5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling.
abstract: The clinical need for novel bronchodilators for the treatment of bronchoconstrictive diseases remains a major medical issue. Modulation of airway smooth muscle (ASM) chloride via GABAA receptor activation to achieve relaxation of precontracted ASM represents a potentially beneficial therapeutic option. Since human ASM GABAA receptors express only the α4- and α5-subunits, there is an opportunity to selectively target ASM GABAA receptors to improve drug efficacy and minimize side effects. Recently, a novel compound (R)-ethyl8-ethynyl-6-(2-fluorophenyl)-4-methyl-4H-benzo[f]imidazo[1,5-a][1,4] diazepine-3-carboxylate (SH-053-2'F-R-CH3) with allosteric selectivity for α5-subunit containing GABAA receptors has become available. We questioned whether this novel GABAA α5-selective ligand relaxes ASM and affects intracellular calcium concentration ([Ca(2+)]i) regulation. Immunohistochemical staining localized the GABAA α5-subunit to human ASM. The selective GABAA α5 ligand SH-053-2'F-R-CH3 relaxes precontracted intact ASM; increases GABA-activated chloride currents in human ASM cells in voltage-clamp electrophysiology studies; and attenuates bradykinin-induced increases in [Ca(2+)]i, store-operated Ca(2+) entry, and methacholine-induced Ca(2+) oscillations in peripheral murine lung slices. In conclusion, selective subunit targeting of endogenous α5-subunit containing GABAA receptors on ASM may represent a novel therapeutic option to treat severe bronchospasm.
authors: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York; gg2125@cumc.columbia.edu.
authors: George
authors: G
authors: Gallos
authors: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York;
authors: Gene T
authors: GT
authors: Yocum
authors: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York;
authors: Matthew E
authors: ME
authors: Siviski
authors: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York;
authors: Peter D
authors: PD
authors: Yim
authors: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York;
authors: Xiao Wen
authors: XW
authors: Fu
authors: Department of Chemistry, University of Wisconsin, Milwaukee, Wisconsin; and.
authors: Michael M
authors: MM
authors: Poe
authors: Department of Chemistry, University of Wisconsin, Milwaukee, Wisconsin; and.
authors: James M
authors: JM
authors: Cook
authors: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York;
authors: Neil
authors: N
authors: Harrison
authors: Department of Cell Physiology and Molecular Biophysics; and Texas Tech University Health Sciences Center, Lubbock, Texas.
authors: Jose
authors: J
authors: Perez-Zoghbi
authors: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York;
authors: Charles W
authors: CW
authors: Emala
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000378:metabolism; D001986:Bronchial Spasm / Q000188:drug therapy; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003975:Diazepam / Q000031:analogs & derivatives* / Q000494:pharmacology; D058785:GABA-A Receptor Agonists / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D009130:Muscle, Smooth / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011963:Receptors, GABA-A / Q000378:metabolism*; D012137:Respiratory System / Q000187:drug effects
chemical_list: D001993:Bronchodilator Agents; D058785:GABA-A Receptor Agonists; C527986:GABRA5 protein, human; D007093:Imidazoles; D011963:Receptors, GABA-A; C571869:SH-053-2'F-R-CH3; D016210:Methacholine Chloride; D003975:Diazepam; D001920:Bradykinin; D002118:Calcium
keywords: GABAA α5-subunit; SH-053-2′F-R-CH3; airway relaxation