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Impact of paroxetine on proximal beta-adrenergic receptor signaling

机译：帕罗西汀对近β-肾上腺素能受体信号传导的影响

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D-adrenergic receptors (beta AR) regulate numerous functions throughout the body, however G protein-coupled receptor kinase (GRK)-dependent desensitization of beta AR has long been recognized as a maladaptive process in the progression of various disease states. Thus, the development of small molecule inhibitors of GRKs for the study of these processes and as potential therapeutics has been at the forefront of recent research efforts. Via structural and biochemical analyses, the selective serotonin reuptake inhibitor (SSRI) paroxetine was identified as a GRK2 inhibitor that enhances PAR-dependent cardiomyocyte and cardiac contractility and reverses cardiac dysfunction and myocardial DAR expression in mouse models of heart failure. Despite these functional outcomes, consistent with diminished beta AR desensitization, the proximal PAR signaling mechanisms sensitive to paroxetine have not been reported. In this study, we aimed to determine whether paroxetine prevents classic beta AR desensitization-related signaling mechanisms at a molecular level. Therefore, via immunoblotting, radioligand binding, fluorescence resonance energy transfer (FRET) and microscopy assays, we have performed an assessment of the effect of paroxetine on proximal beta AR signaling responses. Indeed, paroxetine treatment inhibited ligand-induced beta 2AR phosphorylation in a concentration -dependent manner. Additionally, for both beta 1AR and beta 2AR, paroxetine decreased ligatid-induced beta arrestin2 recruitment and subsequent receptor internalization. Thus, paroxetine inhibits DAR desensitization mechanisms consistent with GRK2 inhibition and provides a useful pharmacological tool for studying these proximal GPCR signaling responses.
机译：D-肾上腺素能受体（Beta Ar）调节整个身体的许多功能，然而，G蛋白偶联受体激酶（GRK）依赖性βAR的脱敏已经被认为是各种疾病状态的进展中的不良过程。因此，在近期研究努力的最前沿，对这些过程进行研究的小分子抑制剂的发展是最近的研究努力的最前沿。通过结构和生化分析，选择性血清素再摄取抑制剂（SSRI）帕罗西汀被鉴定为GRK2抑制剂，可增强依赖于PAR依赖性心肌细胞和心脏收缩性，并在心力衰竭小鼠模型中逆转心脏功能障碍和心肌DIL表达。尽管有这些功能性结果，但尚未符合β静脉脱敏，尚未报道对帕罗西汀敏感的近端分析信号机制。在这项研究中，我们旨在确定帕罗西汀是否可防止分子水平的经典β酰胺相关的信号传导机制。因此，通过免疫印迹，放射性配体结合，荧光共振能量转移（FRET）和显微镜测定，我们已经对帕罗西汀对近端β的信号响应进行了评估。实际上，帕罗西汀治疗以浓度依赖性的方式抑制配体诱导的β2AR磷酸化。另外，对于β1AR和β2AR，帕罗西汀降低了诱导的β诱导2募集和随后的受体内化。因此，帕罗西汀抑制了与GRK2抑制一致的DAR脱敏机制，并提供了用于研究这些近端GPCR信号调速的有用药理学工具。

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