Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA.
Neurobiol Aging. 2011 Oct;32(10):1818-26. doi: 10.1016/j.neurobiolaging.2009.10.017. Epub 2009 Dec 1.
RACK1 (receptor for activated C-kinase 1), an anchoring protein that shuttles activated PKC to cellular membranes, plays an important role in PKC-mediated signal transduction pathways. A significant loss of RACK1 has been found in the brain of aging animals and Alzheimer's disease (AD) patients, which implicates the potential involvement of RACK1 in altered PKC activation associated with dementia. Our previous studies have demonstrated that GABAergic inhibition in prefrontal cortex, which is important for cognitive processes like "working memory", is regulated by muscarinic receptors via a PKC-dependent mechanism, and this effect is impaired by β-amyloid peptide (Aβ). In this study, we found that Aβ oligomers decreased RACK1 distribution in the membrane fraction of cortical neurons. Moreover, overexpression of RACK1 rescued the effect of muscarinic receptors on GABAergic transmission in Aβ-treated cortical cultures in vitro and Aβ-injected cortical neurons in vivo. These results suggest that the Aβ-induced loss of RACK1 distribution in the cell membrane may underlie the Aβ impairment of muscarinic regulation of PKC and GABAergic transmission. Thus, RACK1 provides a potential therapeutic target that can restore some of the impaired cellular processes by Aβ.
RACK1（激活蛋白激酶 C 的受体 1）是一种衔接蛋白，可将激活的蛋白激酶 C 穿梭到细胞膜上，在蛋白激酶 C 介导的信号转导途径中发挥重要作用。在衰老动物和阿尔茨海默病（AD）患者的大脑中发现 RACK1 大量丢失，这表明 RACK1 可能参与了与痴呆相关的 PKC 激活改变。我们之前的研究表明，前额叶皮层中的 GABA 能抑制对于“工作记忆”等认知过程很重要，它通过一种蛋白激酶 C 依赖的机制受到毒蕈碱受体的调节，而这种效应被β-淀粉样肽（Aβ）损害。在这项研究中，我们发现 Aβ 寡聚体减少了皮质神经元质膜部分的 RACK1 分布。此外，RACK1 的过表达可挽救 Aβ 处理的皮质培养物中以及 Aβ 注射的皮质神经元中，毒蕈碱受体对 GABA 能传递的作用。这些结果表明，Aβ 诱导的细胞膜中 RACK1 分布的丢失可能是 Aβ 损害毒蕈碱对 PKC 和 GABA 能传递的调节的基础。因此，RACK1 提供了一个潜在的治疗靶点，通过 Aβ 可以恢复一些受损的细胞过程。
