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Genetics:γ氨基丁酸(GABA)运输分子开关

来源:生命经纬 2009-12-15 09:17

根据一篇发布在Genetics上的文章,亚拉巴马大学的科学家在线虫C.  elegans中识别一种关键的分子开关,其能控制γ氨基丁酸(GABA)的运输。

研究人员表示,他们希望这项研究能够加速癫痫遗传因子的识别。同时,这项研究结果或有助于在未来开发出控制或预防癫痫的新方法。

研究人员使用能影响神经元活性的药物对线虫进行试验,并结合在人类和线虫中共有的遗传因子的DNA变异。结果表明,线虫神经元活性的改变导致了反复的抽搐,这种现象和癫痫表现出的症状是相似的。研究人员在显微镜下观察这些抽搐,并根据试验视频估计神经元改变的严重程度。

然后,研究人员使用绿色荧光蛋白来标记细胞位点,跟踪GABA在神经元中的传递。标记物使得研究人员观察到了一种特殊的遗传因子,其能够导致神经元出现异常的GABA移动,当线虫表现出癫痫症状时。

尽管在新药开发之前还有大量的工作要进行,但这项发现为患有该类疾病的患者带来了新的希望。(生物谷Bioon.com)

生物谷推荐原始出处:

Genetics, Vol. 183, 1357-1372, December 2009 doi:10.1534/genetics.109.106880

Pharmacogenetic Analysis Reveals a Post-Developmental Role for Rac GTPases in Caenorhabditis elegans GABAergic Neurotransmission

Cody J. Locke*,1,2, Bwarenaba B. Kautu*,1, Kalen P. Berry*, S. Kyle Lee*, Kim A. Caldwell*,,3 and Guy A. Caldwell*,,3

* Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama 35487 and  Departments of Neurobiology and Neurology and Center for Neurodegeneration and Experimental Therapeutics, University of Alabama, Birmingham, Alabama 35294
3 Corresponding authors: Department of Biological Sciences, The University of Alabama, Box

The nerve-cell cytoskeleton is essential for the regulation of intrinsic neuronal activity. For example, neuronal migration defects are associated with microtubule regulators, such as LIS1 and dynein, as well as with actin regulators, including Rac GTPases and integrins, and have been thought to underlie epileptic seizures in patients with cortical malformations. However, it is plausible that post-developmental functions of specific cytoskeletal regulators contribute to the more transient nature of aberrant neuronal activity and could be masked by developmental anomalies. Accordingly, our previous results have illuminated functional roles, distinct from developmental contributions, for Caenorhabditis elegans orthologs of LIS1 and dynein in GABAergic synaptic vesicle transport. Here, we report that C. elegans with function-altering mutations in canonical Rac GTPase-signaling-pathway members demonstrated a robust behavioral response to a GABAA receptor antagonist, pentylenetetrazole. Rac mutants also exhibited hypersensitivity to an acetylcholinesterase inhibitor, aldicarb, uncovering deficiencies in inhibitory neurotransmission. RNA interference targeting Rac hypomorphs revealed synergistic interactions between the dynein motor complex and some, but not all, members of Rac-signaling pathways. These genetic interactions are consistent with putative Rac-dependent regulation of actin and microtubule networks and suggest that some cytoskeletal regulators cooperate to uniquely govern neuronal synchrony through dynein-mediated GABAergic vesicle transport in C. elegans.

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