Gallos George, Yocum Gene T, Siviski Matthew E, Yim Peter D, Fu Xiao Wen, Poe Michael M, Cook James M, Harrison Neil, Perez-Zoghbi Jose, Emala Charles W
Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York;
Department of Chemistry, University of Wisconsin, Milwaukee, Wisconsin; and.
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.
对于治疗支气管收缩性疾病的新型支气管扩张剂的临床需求仍然是一个重大的医学问题。通过激活GABAA受体调节气道平滑肌（ASM）氯离子，以实现预收缩ASM的松弛，这代表了一种潜在有益的治疗选择。由于人类ASM GABAA受体仅表达α4和α5亚基，因此有机会选择性地靶向ASM GABAA受体，以提高药物疗效并将副作用降至最低。最近，一种对含α5亚基的GABAA受体具有变构选择性的新型化合物（R）-乙基8-乙炔基-6-（2-氟苯基）-4-甲基-4H-苯并[f]咪唑并[1,5-a][1,4]二氮杂卓-3-羧酸酯（SH-053-2'F-R-CH3）已可获得。我们质疑这种新型GABAAα5选择性配体是否能松弛ASM并影响细胞内钙浓度（[Ca(2+)]i）调节。免疫组织化学染色将GABAAα5亚基定位于人类ASM。选择性GABAAα5配体SH-053-2'F-R-CH3可松弛预收缩的完整ASM；在电压钳电生理研究中增加人类ASM细胞中GABA激活的氯离子电流；并减弱缓激肽诱导的[Ca(2+)]i增加、储存操作的Ca(2+)内流以及乙酰甲胆碱诱导的外周鼠肺切片中的Ca(2+)振荡。总之，选择性靶向ASM上含内源性α5亚基的GABAA受体可能代表一种治疗严重支气管痉挛的新型治疗选择。
