B-Arrestin2 Is Required for BAR Resensitization But Not

β-Arrstins(beta arrestin1&2)是广泛存在的多功能支架蛋白，参与G蛋白偶联受体(GPCR)信号转导。来自模型细胞的证据表明，结合β-拦阻素通过阻断受体G蛋白的相互作用而使激活的GPCRs变得不敏感。然而，在生理环境中，β-阻滞素在β-肾上腺素能受体(β-AR)脱敏和再循环中的作用在很大程度上仍不清楚。在这里，我们证明了小鼠缺乏β-拦阻蛋白2(β-拦阻蛋白2 KO)会导致对两种β-AR亚型刺激的心脏收缩反应的缺陷。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β2-AR磷酸化的显著增加有关。这一出人意料的发现与已建立的研究范式形成鲜明对比，即β-arrestin2促进β-AR脱敏，并反对β-arrestin2的减少或缺失应该提高β-AR信号转导效率的假设。重要的是，腺病毒转导β-Arrstin2能够完全恢复β-AR介导的心肌细胞收缩反应，提示β-AR收缩反应的缺陷是由于β-arrestin2的缺陷，而不是基因敲除引起的非特异性适应性改变。这些结果还表明，β-arrestin2在β-AR再增敏中起重要作用，但在受体脱敏中不起作用。在自发性高血压大鼠(SHR)衰竭的心脏中，β-arrestin2的丰度在心力衰竭发作前显著降低，并且β-arrestin2的下调伴随着对任何一种β-AR亚型刺激的明显减弱的心脏收缩反应，这一事实证实了这一结论。这些发现揭示了β-抑制素2在儿茶酚胺介导的收缩支持中先前未被认识到的关键作用，以及β-精氨酸2下调与心力衰竭发展之间的潜在因果关系。因此，我们的研究可能揭示心力衰竭的新的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.