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 1;308(9):L931-42. doi: 10.1152/ajplung.00107.2014. Epub 2015 Feb 6.


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.

Keywords: GABAA α5-subunit; SH-053-2′F-R-CH3; airway relaxation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bradykinin / metabolism
  • Bronchial Spasm / drug therapy
  • Bronchoconstriction / drug effects
  • Bronchodilator Agents / pharmacology*
  • Calcium / metabolism
  • Cells, Cultured
  • Diazepam / analogs & derivatives*
  • Diazepam / pharmacology
  • GABA-A Receptor Agonists / pharmacology*
  • Guinea Pigs
  • Humans
  • Imidazoles / pharmacology*
  • Ion Channel Gating / drug effects
  • Male
  • Methacholine Chloride / pharmacology
  • Muscle, Smooth / metabolism*
  • Myocytes, Smooth Muscle / drug effects
  • Patch-Clamp Techniques
  • Receptors, GABA-A / metabolism*
  • Respiratory System / drug effects


  • Bronchodilator Agents
  • GABA-A Receptor Agonists
  • GABRA5 protein, human
  • Imidazoles
  • Receptors, GABA-A
  • SH-053-2'F-R-CH3
  • Methacholine Chloride
  • Diazepam
  • Bradykinin
  • Calcium