Selective targeting of the α5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling
Selective targeting of the α5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling
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DOI：
10.1152/ajplung.00107.2014
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发表时间：
2015-05-01
影响因子：
4.9
通讯作者：
Emala, Charles W., Sr.
中科院分区：
文献类型：
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作者：
Gallos, George;Yocum, Gene T.;Emala, Charles W., Sr.
临床对用于治疗支气管收缩疾病的新型支气管扩张剂的需求仍然是一个主要的医学问题。通过 GABA(A) 受体激活调节气道平滑肌 (ASM) 氯化物以实现预收缩 ASM 的松弛，这是一种潜在有益的治疗选择。由于人类 ASM GABA(A) 受体仅表达 α 4 和 α 5 亚基，因此有机会选择性地靶向 ASM GABA(A) 受体，以提高药物疗效并最大限度地减少副作用。最近，一种新型化合物（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-3-羧酸酯（SH-053-2'F-R-CH3）对含有GABA（A）受体的α5亚基具有变构选择性。我们质疑这种新型 GABA(A) α 5 选择性配体是否会放松 ASM 并影响细胞内钙浓度 ([Ca2+](i)) 调节。免疫组织化学染色将 GABA(A) α 5 亚基定位于人 ASM。选择性 GABA(A) α 5 配体 SH-053-2'FR-CH3 松弛预收缩的完整 ASM；在电压钳电生理学研究中增加人 ASM 细胞中 GABA 激活的氯电流；并减弱外周小鼠肺切片中缓激肽诱导的 [Ca2+](i) 增加、钙池操纵的 Ca2+ 进入和醋甲胆碱诱导的 Ca2+ 振荡。总之，选择性亚基靶向 ASM 上含有 GABA(A) 受体的内源性 α5 亚基可能代表治疗严重支气管痉挛的新治疗选择。
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 GABA(A) receptor activation to achieve relaxation of precontracted ASM represents a potentially beneficial therapeutic option. Since human ASM GABA(A) receptors express only the alpha 4- and alpha 5-subunits, there is an opportunity to selectively target ASM GABA(A) 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 alpha 5-subunit containing GABA(A) receptors has become available. We questioned whether this novel GABA(A) alpha 5-selective ligand relaxes ASM and affects intracellular calcium concentration ([Ca2+](i)) regulation. Immunohistochemical staining localized the GABA(A) alpha 5-subunit to human ASM. The selective GABA(A) alpha 5 ligand SH-053-2'FR-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 [Ca2+](i), store-operated Ca2+ entry, and methacholine-induced Ca2+ oscillations in peripheral murine lung slices. In conclusion, selective subunit targeting of endogenous alpha 5-subunit containing GABA(A) receptors on ASM may represent a novel therapeutic option to treat severe bronchospasm.