Abstract β adrenergic receptors mediate effects via activation of G proteins, transactivation of membrane growth factor receptors, or β adrenergic receptor-β arrestin-facilitated scaffold-mediated signaling. Agonist occupancy of the β adrenergic receptor induces desensitization by promoting β adrenergic receptor kinase phosphorylation of the carboxyl terminal domain, facilitating binding of the amino terminal of the β arrestin, which sterically inhibits interactions between β adrenergic receptors and G proteins and induces clathrin-coated pit-mediated receptor endocytosis. Scaffold formation promoted by β arrestin binding to the β adrenergic receptor activates extracellular regulated kinase 1/2 in a manner which elicits cytosolic retention of, and prevents promotion of nuclear transcriptional activity by, mitogen-activated protein kinase. The β adrenergic receptor kinase also interacts with a yet to be determined microsomal membrane protein via high-affinity electrostatic interactions. We evaluate β adrenergic receptor structure, function, and downstream signaling and β arrestin-mediated desensitization, receptor endocytosis, and scaffold-facilitated signal transduction in order to illumine therapeutic strategies designed to modulate these pathways. We trust these approaches may arm us with the capacity to selectively modulate signal transduction pathways regulating cellular proliferation, immunogenicity, angiogenesis, and invasive and metastatic potential implicated in cancer initiation, promotion, and progression.

中文翻译：

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β-肾上腺素能受体的结构和功能：指导恶性肿瘤治疗新策略开发的分子见解

摘要 β 肾上腺素能受体通过 G 蛋白的激活、膜生长因子受体的反式激活或 β 肾上腺素能受体-β抑制素促进的支架介导的信号传导来介导效应。激动剂占据 β 肾上腺素能受体，通过促进 β 肾上腺素能受体激酶羧基末端结构域的磷酸化，促进 β 抑制素氨基末端的结合，从而在空间上抑制 β 肾上腺素能受体与 G 蛋白之间的相互作用并诱导网格蛋白包被的凹坑，从而诱导脱敏介导的受体内吞作用。β抑制蛋白与β肾上腺素能受体结合所促进的支架形成激活细胞外调节激酶1/2，这种方式引起细胞质滞留并阻止丝裂原活化蛋白激酶促进核转录活性。β 肾上腺素能受体激酶还通过高亲和力静电相互作用与尚未确定的微粒体膜蛋白相互作用。我们评估了 β 肾上腺素能受体的结构、功能和下游信号传导以及 β 抑制素介导的脱敏、受体内吞作用和支架促进的信号转导，以阐明旨在调节这些途径的治疗策略。我们相信这些方法可能使我们能够选择性地调节信号转导通路，调节细胞增殖、免疫原性、血管生成以及与癌症发生、促进和进展有关的侵袭和转移潜力。我们评估了 β 肾上腺素能受体的结构、功能和下游信号传导以及 β 抑制素介导的脱敏、受体内吞作用和支架促进的信号转导，以阐明旨在调节这些途径的治疗策略。我们相信这些方法可能使我们能够选择性地调节信号转导通路，调节细胞增殖、免疫原性、血管生成以及与癌症发生、促进和进展有关的侵袭和转移潜力。我们评估了 β 肾上腺素能受体的结构、功能和下游信号传导以及 β 抑制素介导的脱敏、受体内吞作用和支架促进的信号转导，以阐明旨在调节这些途径的治疗策略。我们相信这些方法可能使我们能够选择性地调节信号转导通路，调节细胞增殖、免疫原性、血管生成以及与癌症发生、促进和进展有关的侵袭和转移潜力。