Corticotropin Releasing Factor-Induced CREB Activation in Striatal Neurons Occurs via a Novel Gβγ Signaling Pathway

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 Gαs, 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.促肾上腺皮质激素释放因子（corticotropin-releasing factor, CRF）最初被确认为应激反应的关键组成部分。CRF通过结合两种同源G蛋白偶联受体（G-protein coupled receptors, GPCRs）中的一种——CRF受体1（CRFR1）或CRF受体2（CRFR2）——发挥细胞生物学效应。尽管这类GPCR最初被认为与Gαs亚基偶联，进而激活下游腺苷酸环化酶（adenylyl cyclase, AC）并升高环磷酸腺苷（cAMP）水平，但后续研究证实CRFR家族受体还可偶联并激活诸多其他下游信号级联反应。此外，CRF信号通路可调控多种不同脑区的神经活动，进而影响多种行为表型。纹状体便是其中之一，其包含伏隔核（nucleus accumbens, NAc）。CRF对纹状体依赖的行为具有显著调控作用，例如药物成瘾、伴侣依恋以及天然奖赏行为。近期研究表明，CRF调控的部分行为是通过激活转录因子环腺苷酸应答元件结合蛋白（cAMP response element-binding protein, CREB）实现的。因此，本研究旨在阐明CRF在纹状体神经元中激活CREB的具体信号通路。本文报道了一条全新的神经元信号通路：CRF可通过Gβγ亚基与丝裂原活化蛋白激酶激酶（mitogen-activated protein kinase kinase, MEK）依赖的途径，快速诱导CREB磷酸化水平升高。本研究不仅首次在神经元中证实CRF可激活Gβγ依赖的信号通路，同时也是首个在任何细胞系统中报道Gβγ激活可介导下游CREB磷酸化的研究。此外，本研究还为CRF调控神经元功能的分子机制提供了新的理论视角。