G蛋白βγ亚基介导的磷脂酶A_2激活与β-AR失敏的关系

RELATIONSHIP BETWEEN PHOSPHOLIPASE A_2 ACTIVATION MEDIATED BY G PROTEIN βγ SUBUNIT AND β-ADRENERGIC RECEPTOR DESENSITIZATION

研究异丙基肾上腺素 (ISO)所致的体外培养大鼠肺 β 肾上腺素受体 ( β AR)失敏的机理 ,首先观察了不同浓度和不同作用时间的ISO对大鼠肺 β AR失敏的影响 ,可见ISO所致 β AR失敏呈良好的量 效和时 效关系 ;ISO对磷脂酶A2 (PLA2 )激活也呈时间和剂量依赖性 ,且PLA2 激活比 β AR失敏所需的ISO剂量低 .上述现象可分别被PLA2 特异性抑制剂对溴乙酰酚 (PBA)、地塞米松 (Dex)、Gi蛋白灭活剂百日咳毒素 (PTX)、抗Giα血清和抗Gβγ血清所抑制 ;而 5′ O 3 硫代三磷酸鸟甘 (GTP γ S)则能加重ISO所致β AR失敏和PLA2 激活 .以上结果提示 :体外培养的大鼠肺 β AR在激动剂长时期作用下 ,受体发生的失敏与G蛋白介导的PLA2 激活有关 ,此时β AR的信号转导途径由原来腺苷酸环化酶正偶联转变为G蛋白 βγ亚基介导的PLA2

To elicit the mechanism of β AR coupling to PLA 2 , the relationship between isoproterenol (ISO) induced β AR binding capacity and phospholipase A 2 (PLA 2 ) activation in rat lung tissue is investigated in vitro. β AR down regulation and PLA 2 activation induced by ISO in rat lung tissues display dose and time dependent manner. However, the activation of PLA 2 is more sensitive than β AR down regulation as shown by dose effect. The changes mentioned above are effectively abolished when p bromoacetophenone (PBA), pertussis toxin (PTX), dexamethasone (DEX) ,anti Giα and anti Gβγ serum are involved respectively in the reaction system . On the other hand, the addition of GTP γ S ,which binds to Gα subunit with high affinity and releases free Gβγ, aggravates β AR down regulation and PLA 2 activity during coincubation with ISO. These data suggest that long term treatment of rat lung tissues with ISO can lead to β AR down regulation , while the signal transduction pathway is also switched from adenylate cyclase(AC) positive coupled to PLA 2 activation which is mediated by Gβγ.