Pharmacological blockade of a β2AR-β-arrestin-1 signaling cascade prevents the accumulation of DNA damage in a behavioral stress model
Pharmacological blockade of a β2AR-β-arrestin-1 signaling cascade prevents the accumulation of DNA damage in a behavioral stress model
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DOI：
10.4161/cc.23368
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发表时间：
2013-01-15
期刊：
影响因子：
4.3
通讯作者：
Lefkowitz, Robert J.
中科院分区：
文献类型：
--
作者：
Hara, Makoto R.;Sachs, Benjamin D.;Lefkowitz, Robert J.
众所周知，慢性应激对人类健康有深远的负面影响，并被认为会影响多种疾病状态。然而，应激有害影响的潜在机制在很大程度上仍然未知。已知应激会促进肾上腺素的释放，肾上腺素是一种儿茶酚胺应激激素，能高亲和力地与β(2)-肾上腺素能受体（β(2)ARs）结合。我们先前的研究表明，通过输注异丙肾上腺素对βR - 2 - β - 抑制蛋白 - 1介导的信号通路进行慢性刺激会抑制p53水平并损害基因组完整性。在该通路中，通过β(2)ARs激活的β - 抑制蛋白 - 1促进AKT介导的Mdm2激活，并作为一种分子支架促进E3 - 泛素连接酶Mdm2对p53的结合和降解。在此，我们发现小鼠的慢性束缚应激重现了异丙肾上腺素输注降低p53水平的效应，并导致大脑额叶皮质中DNA损伤的累积，而β - 阻滞剂普萘洛尔以及β - 抑制蛋白 - 1的基因缺失可消除这两种效应。这些数据表明，β2AR - β - 抑制蛋白 - 1信号通路可能是一个有吸引力的治疗靶点，用于预防应激相关疾病治疗中应激的一些负面后果。
Chronic stress is known to have a profound negative impact on human health and has been suggested to influence a number of disease states. However, the mechanisms underlying the deleterious effects of stress remain largely unknown. Stress is known to promote the release of epinephrine, a catecholamine stress hormone that binds to beta(2)-adrenergic receptors (beta(2)ARs) with high affinity. Our previous work has demonstrated that chronic stimulation of a beta R-2-beta-arrestin-1-mediated signaling pathway by infusion of isoproterenol suppresses p53 levels and impairs genomic integrity. In this pathway, beta-arrestin-1, which is activated via beta(2)ARs, facilitates the AKT-mediated activation of Mdm2 and functions as a molecular scaffold to promote the binding and degradation of p53 by the E3-ubiquitin ligase, Mdm2. Here, we show that chronic restraint stress in mice recapitulates the effects of isoproterenol infusion to reduce p53 levels and results in the accumulation of DNA damage in the frontal cortex of the brain, two effects that are abrogated by the beta-blocker, propranolol and by genetic deletion of beta-arrestin-1. These data suggest that the beta 2AR-beta-arrestin-1 signaling pathway may represent an attractive therapeutic target to prevent some of the negative consequences of stress in the treatment of stress-related disorders.