Ligand-induced overexpression of a constitutively active beta2-adrenergic receptor: pharmacological creation of a phenotype in transgenic mice.
Ligand-induced overexpression of a constitutively active beta2-adrenergic receptor: pharmacological creation of a phenotype in transgenic mice.
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配体诱导的组成型活性β2-肾上腺素受体的过度表达：转基因小鼠表型的药理学创造。
DOI：
10.1073/pnas.94.1.137
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发表时间：
1997
影响因子：
11.1
通讯作者：
Lefkowitz,RJ
中科院分区：
文献类型：
--
作者：
Samama,P;Bond,RA;Rockman,HA;Milano,CA;Lefkowitz,RJ
野生型人β2肾上腺素能受体在小鼠心脏中的转基因过表达（40- 100倍）导致心脏收缩力显著增加，这显然是由于该受体固有的低水平自发（即不依赖激动剂）活性。在这里，我们报告了表达突变的构成活性受体（CAM）的转基因小鼠，由于其适度表达（比内源性心脏β-肾上腺素能受体水平高3倍），没有表现出这种表型。令人惊讶的是，用各种β-肾上腺素能受体配体治疗动物，通过稳定CAM β2-肾上腺素能受体蛋白，导致CAM β2-肾上腺素能受体表达增加50倍。受体上调反过来导致腺苷酸环化酶活性显著增加，体外确定心房张力，体内确定心脏收缩性指标。这些结果说明了调节生理反应的新机制，即配体诱导的组成活性但本质上不稳定的蛋白质的稳定。
Transgenic overexpression (40- to 100-fold) of the wild-type human β2-adrenergic receptor in the hearts of mice leads to a marked increase in cardiac contractility, which is apparently due to the low level of spontaneous (i.e., agonist-independent) activity inherent in the receptor. Here we report that transgenic mice expressing a mutated constitutively active form of the receptor (CAM) show no such phenotype, owing to its modest expression (3-fold above endogenous cardiac β-adrenergic receptor levels). Surprisingly, treatment of the animals with a variety of β-adrenergic receptor ligands leads to a 50-fold increase in CAM β2-adrenergic receptor expression, by stabilizing the CAM β2-adrenergic receptor protein. Receptor up-regulation leads in turn to marked increases in adenylate cyclase activity, atrial tension determinedin vitro, and indices of cardiac contractility determinedin vivo. These results illustrate a novel mechanism for regulating physiological responses, i.e., ligand-induced stabilization of a constitutively active but inherently unstable protein.