Department of Biological Sciences, the State University of New York at Buffalo, Buffalo, New York, USA.
J Neurochem. 2018 Feb;144(4):466-482. doi: 10.1111/jnc.14230. Epub 2017 Oct 18.
Proper neuronal function requires essential biological cargoes to be packaged within membranous vesicles and transported, intracellularly, through the extensive outgrowth of axonal and dendritic fibers. The precise spatiotemporal movement of these cargoes is vital for neuronal survival and, thus, is highly regulated. In this study we test how the axonal movement of a neuropeptide-containing dense-core vesicle (DCV) responds to alcohol stressors. We found that ethanol induces a strong anterograde bias in vesicle movement. Low doses of ethanol stimulate the anterograde movement of neuropeptide-DCV while high doses inhibit bi-directional movement. This process required the presence of functional kinesin-1 motors as reduction in kinesin prevented the ethanol-induced stimulation of the anterograde movement of neuropeptide-DCV. Furthermore, expression of inactive glycogen synthase kinase 3 (GSK-3β) also prevented ethanol-induced stimulation of neuropeptide-DCV movement, similar to pharmacological inhibition of GSK-3β with lithium. Conversely, inhibition of PI3K/AKT signaling with wortmannin led to a partial prevention of ethanol-stimulated transport of neuropeptide-DCV. Taken together, we conclude that GSK-3β signaling mediates the stimulatory effects of ethanol. Therefore, our study provides new insight into the physiological response of the axonal movement of neuropeptide-DCV to exogenous stressors. Cover Image for this Issue: doi: 10.1111/jnc.14165.
神经元的正常功能需要将重要的生物货物包装在膜泡内,并通过轴突和树突纤维的广泛延伸在细胞内进行运输。这些货物的精确时空运动对神经元的存活至关重要,因此受到高度调控。在这项研究中,我们测试了含有神经肽的致密核心囊泡(DCV)的轴突运动如何响应酒精应激源。我们发现,乙醇诱导囊泡运动强烈的正向偏倚。低剂量的乙醇刺激神经肽-DCV 的正向运动,而高剂量的乙醇抑制双向运动。这个过程需要功能性的驱动蛋白-1 马达的存在,因为驱动蛋白的减少阻止了乙醇诱导的神经肽-DCV 正向运动的刺激。此外,表达无活性的糖原合酶激酶 3(GSK-3β)也阻止了乙醇诱导的神经肽-DCV 运动的刺激,这与用锂抑制 GSK-3β 的药理学作用相似。相反,用渥曼青霉素抑制 PI3K/AKT 信号通路会导致部分阻止神经肽-DCV 的乙醇刺激运输。总之,我们得出结论,GSK-3β 信号转导介导了乙醇的刺激作用。因此,我们的研究为神经肽-DCV 的轴突运动对外源性应激源的生理反应提供了新的见解。本期的封面图片:doi: 10.1111/jnc.14165.