B-Arrestin2 Is Required for BAR Resensitization But Not

β -阻滞蛋白（β -阻滞蛋白1&2）是一种普遍存在的多功能支架蛋白，参与G蛋白偶联受体（GPCR）信号传导。来自模型细胞的证据表明，β -阻滞蛋白的结合通过阻断受体G蛋白的相互作用使激活的gpcr脱敏。然而，在生理环境下，β -抑制素在β -肾上腺素能受体（β -ar）脱敏和再循环中的功能作用仍然难以捉摸。在这里，我们证明了小鼠β -arrestin2的缺乏（β -arrestin2 KO）导致对两种β -ar亚型刺激的心脏收缩反应缺陷。β - ar反应性的降低与这些受体的密度或配体结合特性的改变无关，但与β - ar磷酸化的显著增加有关。这一意想不到的发现与β -arrestin2促进β -ar脱敏的既定范式形成鲜明对比，并反驳了β -arrestin2的减少或缺乏应该提高β -ar信号传导效率的假设。重要的是，β -arrestin2的腺病毒基因转移能够完全恢复β -ar介导的心肌细胞收缩反应，这表明β -ar收缩反应的缺陷是由于β -arrestin2的缺乏，而不是基因敲除相关的非特异性适应性变化。这些结果也表明β -arrestin2在β -ar再敏中起重要作用，但在受体脱敏中不起作用。在自发性高血压大鼠（SHR）的衰竭心脏中，β -arrestin2的丰度在心力衰竭发作前明显下降，并且β -arrestin2的下调伴随着对β -ar亚型刺激的心脏收缩反应明显减弱，这一事实证实了这一结论。这些发现揭示了β -arresin2在儿茶酚胺介导的收缩支持中的关键作用，以及β -arresin2下调与心力衰竭发展之间的潜在因果关系。因此，我们的研究可能会揭示心力衰竭的新病因和潜在的治疗靶点。

Beta-arrstins (beta arrestin1&2) are ubiquitous multifunctional scaffold proteins involved in G protein coupled receptor (GPCR) signaling. Evidence from model cells suggests that binding of beta-arrestins desensitizes activated GPCRs by blocking receptor G protein interaction. However, the functional role of beta-arrestins in beta-adrenergic receptor (beta-AR) desensitization and recycling in physiological contexts remains largely elusive. Here, we demonstrate that deficiency of beta-arrestin2 in mice (beta-arrestin2 KO) causes defects in cardiac contractile response to stimulation of both beta-AR subtypes. The reduced beta-AR responsiveness is not associated with alterations in the densities or ligand binding properties of these receptors, but is related to a marked increase in beta2-AR phosphorylation. This unexpected finding is in sharp contrast to the established paradigm that beta-arrestin2 promotes beta-AR desensitization, and argues against the hypothesis that reduction or deficiency of beta-arrestin2 should enhance beta-AR signaling efficiency. Importantly, adenoviral gene transfer of beta-arrstin2 is able to fully restore beta-AR mediated contractile response in cardiomyocytes from beta-arrestin2 KO mice, indicating that the defect of beta-AR contractile response is attributable to the deficiency of beta-arrestin2 rather that the gene knockout associated nonspecific adaptive changes. These results also suggest that beta-arrestin2 plays an essential role in beta-AR resensitiztion, but not in the receptor desensitization. This conclusion is corroborated by the fact that in the failing hearts from spontaneous hypertensive rats (SHR), the abundance of beta-arrestin2 is markedly decreased before the onset of heart failure, and that the downregulation of beta-arrestin2 is accompanied by overtly attenuated cardiac contractile response to either beta-AR subtype stimulation. These findings have revealed a previously unrecognized crucial role of beta-arrestin2 in catecholamine-mediated contractile support and a potential causal relation between downregulation of beta-arresin2 and the development of heart failure. Thus, our study might reveals novel causal factors and potential therapeutic targets of heart failure.