A homolog of FHM2 is involved in modulation of excitatory neurotransmission by serotonin in C. elegans.
A homolog of FHM2 is involved in modulation of excitatory neurotransmission by serotonin in C. elegans.
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DOI：
10.1371/journal.pone.0010368
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发表时间：
2010-04-28
期刊：
影响因子：
3.7
通讯作者：
Sze JY
中科院分区：
文献类型：
--
作者：
Govorunova EG;Moussaif M;Kullyev A;Nguyen KC;McDonald TV;Hall DH;Sze JY
线虫Eat-6基因编码Na+，K+-ATPaseα亚基，是家族性偏瘫候选基因FHM2的同源基因。偏头痛是与5-羟色胺能障碍有关的最常见的神经系统疾病。我们试图以线虫作为遗传模型来研究偏头痛的病理生理机制及其与5-羟色胺(5-HT)信号的关系。在线虫中，外源5-羟色胺可抑制乙酰胆碱酯酶抑制剂灭双威引起的瘫痪。我们发现EAT-6(Ad467)突变或RNAi增加了敌敌畏的敏感性，并导致对5-HT治疗的完全抵抗，表明Eat-6是耦合5-HT信号和ACh神经传递途径的一个组成部分。虽然Eat-6在体壁NMJ中的突触后作用已被充分证实，但我们发现Eat-6还可能另外调节突触前ACh神经传递。我们发现EAT-6在腹髓ACh运动神经元中表达，并且在ACh神经元中Eat-6的细胞特异性RNAi导致了对敌百威的超敏反应。电子显微镜显示，在Eat-6(Ad467)突变体中，ACh神经元中的突触小泡数量增加。遗传分析表明，EAT-6与EGL-30 GαQ、EGL-8磷脂酶C和SLO-1 BK通道信号相互作用调节ACh神经传递，Eat-6功能减弱或过度都可能导致ACh神经传递增加。对EAT-6和5-羟色胺受体相互作用的研究表明，5-羟色胺对NMJ既有刺激作用，也有抑制作用。我们发现抑制性和刺激性5-羟色胺信号分别来自不同的5-羟色胺神经元。EAT-6在5-羟色胺调节兴奋性神经传递中的作用可能为5-羟色胺受体药物治疗偏头痛的疗效提供遗传学解释。
The C. elegans eat-6 gene encodes a Na+, K+-ATPase α subunit and is a homolog of the familial hemiplegic migraine candidate gene FHM2. Migraine is the most common neurological disorder linked to serotonergic dysfunction. We sought to study the pathophysiological mechanisms of migraine and their relation to serotonin (5-HT) signaling using C. elegans as a genetic model. In C. elegans, exogenous 5-HT inhibits paralysis induced by the acetylcholinesterase inhibitor aldicarb. We found that the eat-6(ad467) mutation or RNAi of eat-6 increases aldicarb sensitivity and causes complete resistance to 5-HT treatment, indicating that EAT-6 is a component of the pathway that couples 5-HT signaling and ACh neurotransmission. While a postsynaptic role of EAT-6 at the bodywall NMJs has been well established, we found that EAT-6 may in addition regulate presynaptic ACh neurotransmission. We show that eat-6 is expressed in ventral cord ACh motor neurons, and that cell-specific RNAi of eat-6 in the ACh neurons leads to hypersensitivity to aldicarb. Electron microscopy showed an increased number of synaptic vesicles in the ACh neurons in the eat-6(ad467) mutant. Genetic analyses suggest that EAT-6 interacts with EGL-30 Gαq, EGL-8 phospholipase C and SLO-1 BK channel signaling to modulate ACh neurotransmission and that either reduced or excessive EAT-6 function may lead to increased ACh neurotransmission. Study of the interaction between eat-6 and 5-HT receptors revealed both stimulatory and inhibitory 5-HT inputs to the NMJs. We show that the inhibitory and stimulatory 5-HT signals arise from distinct 5-HT neurons. The role of eat-6 in modulation of excitatory neurotransmission by 5-HT may provide a genetic explanation for the therapeutic effects of the drugs targeting 5-HT receptors in the treatment of migraine patients.
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影响因子：
16.2
作者：
Brundage, L;Avery, L;Simon, MI
通讯作者：
Simon, MI
影响因子：
3.3
作者：
Dempsey, CM;Mackenzie, SM;Sze, JY
通讯作者：
Sze, JY
影响因子：
30.8
作者：
De Fusco, M;Marconi, R;Casari, G
通讯作者：
Casari, G
影响因子：
3.5
作者：
Doi, Motomichi;Iwasaki, Kouichi
通讯作者：
Iwasaki, Kouichi
DOI：
10.1523/jneurosci.4585-08.2009
发表时间：
2009-02-04
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Harris GP;Hapiak VM;Wragg RT;Miller SB;Hughes LJ;Hobson RJ;Steven R;Bamber B;Komuniecki RW
通讯作者：
Komuniecki RW