Selective targeting of the α5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling. Am J Physiol Lung Cell Mol Physiol 2015 May 01;308(9):L931-42
Date
02/11/2015Pubmed ID
25659897Pubmed Central ID
PMC4421780DOI
10.1152/ajplung.00107.2014Scopus ID
2-s2.0-84929662877 (requires institutional sign-in at Scopus site) 41 CitationsAbstract
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.
Author List
Gallos G, Yocum GT, Siviski ME, Yim PD, Fu XW, Poe MM, Cook JM, Harrison N, Perez-Zoghbi J, Emala CW SrAuthor
James M. Cook PhD University Distinguished Professor in the Chemistry and Biochemistry department at University of Wisconsin - MilwaukeeMESH terms used to index this publication - Major topics in bold
AnimalsBradykinin
Bronchial Spasm
Bronchoconstriction
Bronchodilator Agents
Calcium
Cells, Cultured
Diazepam
GABA-A Receptor Agonists
Guinea Pigs
Humans
Imidazoles
Ion Channel Gating
Male
Methacholine Chloride
Muscle, Smooth
Myocytes, Smooth Muscle
Patch-Clamp Techniques
Receptors, GABA-A
Respiratory System
