点击显示 收起
在急性哮喘发作期间，调控平滑肌收缩的分子是呼吸道反应的重要决定因素。在哮喘急性发作期间，各种“触发器”包括病毒疾病和过敏原均可引起呼吸道急性收缩，导致危及生命的呼吸危机，甚至是死亡。
加州大学旧金山分校研究人员Mallar Bhattacharya医学博士实验室已经确定了一种新的因素，能阻断哮喘有关的呼吸道平滑肌收缩。
Bhattacharya和他的同事首次发现缺乏IQGAP1基因的小鼠在机械通气过程中对气流的阻力增加，然后他们发现从IQGAP1基因敲除小鼠解剖获得的呼吸道比正常小鼠有着更明显的收缩现象。
据报道在Journal of Clinical Investigation杂志上的研究，这些数据表明IQGAP1蛋白通常可以防止呼吸道收缩。为了辨别IQGAP1“放松”呼吸道的作用机理，作者探讨了RhoA蛋白是否可能在其中发挥作用。IQGAP1已知与RhoA交互作用，而RhoA是气管收缩的重要激活剂。
此外，研究小组发现这些缺乏IQGAP1基因的小鼠气管平滑肌RhoA的活化增加。此外，他们发现IQGAP1可充当“支架”，将RhoA“放置”于它的抑制因子p190A-RhoGAP附近，后者通常抑制RhoA的活性。
这些研究结果揭示了在平滑肌收缩过程中，调节RhoA的活化是由IQGAP1“精心策划”的。 进一步剖析这一途径，研究人员希望能够发现，IQGAP1和其他分子的表达可以有针对性地进行靶向作用，并以此来干预治疗哮喘。
IQGAP1-dependent scaffold suppresses RhoA and inhibits airway smooth muscle contraction
Mallar Bhattacharya,et al.
The intracellular scaffold protein IQGAP1 supports protein complexes in conjunction with numerous binding partners involved in multiple cellular processes. Here, we determined that IQGAP1 modulates airway smooth muscle contractility. Compared with WT controls, at baseline as well as after immune sensitization and challenge, Iqgap1–/– mice had higher airway responsiveness. Tracheal rings from Iqgap1–/– mice generated greater agonist-induced contractile force, even after removal of the epithelium. RhoA, a regulator of airway smooth muscle contractility, was activated in airway smooth muscle lysates from Iqgap1–/– mice. Likewise, knockdown of IQGAP1 in primary human airway smooth muscle cells increased RhoA activity. Immunoprecipitation studies indicated that IQGAP1 binds to both RhoA and p190A-RhoGAP, a GTPase-activating protein that normally inhibits RhoA activation. Proximity ligation assays in primary airway human smooth muscle cells and mouse tracheal sections revealed colocalization of p190A-RhoGAP and RhoA; however, these proteins did not colocalize in IQGAP1 knockdown cells or in Iqgap1–/– trachea. Compared with healthy controls, human subjects with asthma had decreased IQGAP1 expression in airway biopsies. Together, these data demonstrate that IQGAP1 acts as a scaffold that colocalizes p190A-RhoGAP and RhoA, inactivating RhoA and suppressing airway smooth muscle contraction. Furthermore, our results suggest that IQGAP1 has the potential to modulate airway contraction severity in acute asthma.
转载地址：http://news.bioon.com/article/6660283.html
