尽管β1和β2亚型肾上腺素能受体在结构和功能上十 分相似，作者最近的研究 显示这两种受体亚型在心肌细胞上的信号传递机制有很大的不同。β1受体激活后，启动 经典的刺激性G蛋白-腺苷酸环化酶-环磷酸腺苷-蛋白激酶A的线性信号传导途径；而β 2受体除与刺激性G蛋白耦联外，还与抑制性G蛋白，Gi2和Gi3，耦联。β2受 体与抑制性G蛋白 的耦联在很大程度上决定了β受体亚型在心脏钙调控、收缩力、环磷酸腺苷水平和蛋白磷 酸 化上的不同作用。β2受体激活所引起的细胞内钙和收缩力的增加与细胞内环磷酸腺苷的 增加和胞浆蛋白磷酸化有明显的脱节。这主要由于抑制性G蛋白激活的蛋白脱磷酸酶可以使 β2受体诱导的环磷酸腺苷-蛋白激酶A的作用局限于细胞质膜上。这种格局化作用，使公 用的第二信使，环磷酸腺苷，在不同的β受体亚型激活时，选择性地执行不同的功能。新的 证 据表明，β受体亚型不仅在激动剂激活时表现不同，而且自发激活的能力也不同。另外，自 发激活的β2受体和激动剂激活的β2受体在细胞内信号传递和靶蛋白的特异性上都不同 。这些发现不仅进一步揭示了β受体亚型在信号传递上的多样性和特异性，而且为理解β受 体亚型在健康和疾病状态下的调节和功能提供了新的线索。%Although β1-adrenergic receptor (β1-AR) and β2- AR share a high degree of structural and functional similarities, our recent stu dies have revealed distinctive β-AR subtype signaling mechanisms in cardiac myocytes. While the classical linear stimulatory G protein (Gs)-adenylyl cyclase-cAMP-protein kinase A (PKA) signaling casc ade has been corroborated for β1-AR stimulation, the β2-AR signaling pathwa y bifurcates at the very first postreceptor step, the G protein level. In addition to Gs, β2-AR cou ples to pertussis toxin-sensitive inhibitory G protein (Gi), proteins Gi2 and Gi3. The coupling of β2-AR to Gi proteins mediates, to a large extent, the differential actions of the β-A R subtypes on cardiac Ca2+ handling, contractility, cAMP accumulation, and PKA-mediated protein phosphorylation. There is an apparent dissociation of β2-AR-induced augment ations of the intracellular Ca2+ (Cai) transient and contractility from cAMP p roduction and PKA-dependent cytoplasmic protein phosphorylation. This can be largely explained by Gi-protein phosphatase dependent functional compartmentalization of the β2-AR- directed cAMP/PKA signaling to the sarcolemmal microdomain. This compartmentalization allows the common second messenger, cAMP, to perform selective functions during β-AR subtype stimulation. Emerging evidence also points to distinctive property of β-AR subtypes to undergo spontaneous activation. Furthermore, spontaneously activated β2-AR is different from agonist-activated β2-AR in intracellular signaling and ta rget protein specificity. These findings not only reveal the diversity and specificity of β -AR subtype signaling, but also provide new insights for understanding the differential regu lation and functionality of β-AR subtypes in healthy and diseased hearts.
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