Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota, United States of America.
PLoS One. 2011 Mar 23;6(3):e18114. doi: 10.1371/journal.pone.0018114.
The peptide corticotropin-releasing factor (CRF) was initially identified as a critical component of the stress response. CRF exerts its cellular effects by binding to one of two cognate G-protein coupled receptors (GPCRs), CRF receptor 1 (CRFR1) or 2 (CRFR2). While these GPCRs were originally characterized as being coupled to Gα(s), leading to downstream activation of adenylyl cyclase (AC) and subsequent increases in cAMP, it has since become clear that CRFRs couple to and activate numerous other downstream signaling cascades. In addition, CRF signaling influences the activity of many diverse brain regions, affecting a variety of behaviors. One of these regions is the striatum, including the nucleus accumbens (NAc). CRF exerts profound effects on striatal-dependent behaviors such as drug addiction, pair-bonding, and natural reward. Recent data indicate that at least some of these behaviors regulated by CRF are mediated through CRF activation of the transcription factor CREB. Thus, we aimed to elucidate the signaling pathway by which CRF activates CREB in striatal neurons. Here we describe a novel neuronal signaling pathway whereby CRF leads to a rapid Gβγ- and MEK-dependent increase in CREB phosphorylation. These data are the first descriptions of CRF leading to activation of a Gβγ-dependent signaling pathway in neurons, as well as the first description of Gβγ activation leading to downstream CREB phosphorylation in any cellular system. Additionally, these data provide additional insight into the mechanisms by which CRF can regulate neuronal function.
肽促肾上腺皮质释放因子（CRF）最初被鉴定为应激反应的关键组成部分。CRF 通过与两种同源 G 蛋白偶联受体（GPCR）之一结合发挥其细胞作用，即 CRF 受体 1（CRFR1）或 2（CRFR2）。虽然这些 GPCR 最初被表征为与 Gα(s)偶联，导致下游腺苷酸环化酶（AC）的激活和随后 cAMP 的增加，但后来清楚的是，CRFR 与许多其他下游信号级联偶联并激活。此外，CRF 信号影响许多不同脑区的活动，影响各种行为。其中一个区域是纹状体，包括伏隔核（NAc）。CRF 对纹状体依赖的行为产生深远影响，如成瘾、配对结合和自然奖励。最近的数据表明，CRF 调节的至少一些这些行为是通过 CRF 激活转录因子 CREB 介导的。因此，我们旨在阐明 CRF 在纹状体神经元中激活 CREB 的信号通路。在这里，我们描述了一种新的神经元信号通路，其中 CRF 导致 CREB 磷酸化的快速 Gβγ-和 MEK 依赖性增加。这些数据首次描述了 CRF 在神经元中导致 Gβγ 依赖性信号通路的激活，以及 Gβγ 激活导致任何细胞系统中下游 CREB 磷酸化的首次描述。此外，这些数据为 CRF 调节神经元功能的机制提供了更多的见解。
