Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA.
Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):21028-33. doi: 10.1073/pnas.1004169107. Epub 2010 Nov 15.
G protein-coupled receptors (GPCRs), the largest family of signaling receptors expressed in the CNS, mediate the neuropsychiatric effects of a diverse range of clinically relevant drugs. It is increasingly clear that GPCRs can activate distinct G protein-dependent and -independent transduction pathway(s), and that certain drugs differ in the ability to regulate distinct signaling mechanisms linked to the same receptors. A fundamental question in neuropharmacology is whether such "biased agonism" occurs in physiologically relevant neurons and with endogenous receptors. Here we show that propranolol and carvedilol, two β-blocker drugs that inhibit β-adrenergic signaling via heterotrimeric G proteins, function in hippocampal pyramidal neurons as potent and selective activators of an alternate receptor-linked calcium signaling pathway mediated by β-arrestin-2 and ERK1/2. Our results support the emerging view of β-arrestin-biased agonism as a significant mechanism of drug action and do so in CNS-derived neurons expressing only native receptors.
G 蛋白偶联受体（GPCRs）是中枢神经系统中表达的最大的信号转导受体家族，介导多种临床相关药物的神经精神作用。越来越清楚的是，GPCR 可以激活不同的依赖 G 蛋白和非依赖 G 蛋白的转导途径，并且某些药物在调节与同一受体相关的不同信号机制的能力上存在差异。神经药理学中的一个基本问题是，这种“偏向激动”是否发生在生理相关的神经元和内源性受体中。在这里，我们表明，普萘洛尔和卡维地洛，两种通过异三聚体 G 蛋白抑制β-肾上腺素能信号的β-受体阻滞剂药物，在海马锥体神经元中作为由β-arrestin-2 和 ERK1/2 介导的替代受体相关钙信号转导途径的有效且选择性激活剂发挥作用。我们的结果支持β-arrestin-偏向激动作为药物作用的重要机制的新兴观点，并且在仅表达天然受体的中枢神经系统来源的神经元中也是如此。
