Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.
J Neurochem. 2011 Mar;116(6):984-95. doi: 10.1111/j.1471-4159.2010.07137.x. Epub 2011 Jan 19.
Monoamine action in the dorsal striatum and nucleus accumbens plays essential roles in striatal physiology. Although research often focuses on dopamine and its receptors, norepinephrine (NE) and adrenergic receptors are also crucial in regulating striatal function. While noradrenergic neurotransmission has been identified in the striatum, little is known regarding the signaling pathways activated by β-adrenergic receptors in this brain region. Using cultured striatal neurons, we characterized a novel signaling pathway by which activation of β1-adrenergic receptors leads to the rapid phosphorylation of cAMP response element binding protein (CREB), a transcription-factor implicated as a molecular switch underlying long-term changes in brain function. NE-mediated CREB phosphorylation requires β1-adrenergic receptor stimulation of a receptor tyrosine kinase, ultimately leading to the activation of a Ras/Raf/MEK/MAPK/MSK signaling pathway. Activation of β1-adrenergic receptors also induces CRE-dependent transcription and increased c-fos expression. In addition, stimulation of β1-adrenergic receptors produces cAMP production, but surprisingly, β1-adrenergic receptor activation of adenylyl cyclase was not functionally linked to rapid CREB phosphorylation. These findings demonstrate that activation of β1-adrenergic receptors on striatal neurons can stimulate two distinct signaling pathways. These adrenergic actions can produce long-term changes in gene expression, as well as rapidly modulate cellular physiology. By elucidating the mechanisms by which NE and β1-adrenergic receptor activation affects striatal physiology, we provide the means to more fully understand the role of monoamines in modulating striatal function, specifically how NE and β1-adrenergic receptors may affect striatal physiology.
背侧纹状体和伏隔核中的单胺能作用对纹状体生理学起着至关重要的作用。尽管研究通常集中在多巴胺及其受体上，但去甲肾上腺素（NE）和肾上腺素能受体在调节纹状体功能方面也至关重要。虽然已经在纹状体中鉴定出了去甲肾上腺素能神经传递，但对于该脑区β-肾上腺素受体激活的信号通路知之甚少。使用培养的纹状体神经元，我们描述了一种新的信号通路，即β1-肾上腺素受体的激活导致 cAMP 反应元件结合蛋白（CREB）的快速磷酸化，CREB 作为分子开关，作为大脑功能长期变化的基础，是一种转录因子。NE 介导的 CREB 磷酸化需要β1-肾上腺素受体刺激受体酪氨酸激酶，最终导致 Ras/Raf/MEK/MAPK/MSK 信号通路的激活。β1-肾上腺素受体的激活还诱导 CRE 依赖性转录和 c-fos 表达的增加。此外，β1-肾上腺素受体的刺激会产生 cAMP 产生，但令人惊讶的是，β1-肾上腺素受体激活腺苷酸环化酶与快速 CREB 磷酸化在功能上没有联系。这些发现表明，纹状体神经元上β1-肾上腺素受体的激活可以刺激两种不同的信号通路。这些肾上腺素能作用可以产生基因表达的长期变化，以及快速调节细胞生理学。通过阐明 NE 和β1-肾上腺素受体激活如何影响纹状体生理学的机制，我们提供了更全面地理解单胺类物质调节纹状体功能的手段，特别是 NE 和β1-肾上腺素受体如何影响纹状体生理学。
