Presynaptic Targeting of α4β2 Nicotinic Acetylcholine Receptors Is Regulated by Neurexin-1β
Presynaptic Targeting of α4β2 Nicotinic Acetylcholine Receptors Is Regulated by Neurexin-1β
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DOI：
10.1074/jbc.m109.017384
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发表时间：
2009-08-28
影响因子：
4.8
通讯作者：
Anand, Rene
中科院分区：
文献类型：
--
作者：
Cheng, Shi-Bin;Amici, Stephanie A.;Anand, Rene
神经元烟碱乙酰胆碱受体（AChR）的靶向机制，其在神经元突触的功能组织的关键，还没有很好地理解。我们已经确定了一个新的功能之间的联系α 4 β 2乙酰胆碱受体和突触前细胞粘附分子，neurexin-1 β。在非神经元tsA 201细胞中，重组neurexin-1 β和成熟α 4 β 2 AChR形成复合物。α 4 β 2 AChR和neurexin-1 β也从大鼠脑裂解物中共免疫沉淀。当外源性α 4 β 2 AChR和neurexin-1 β在海马神经元中共表达时，它们强烈靶向这些神经元和共培养的表达neurexin-1 β的突触后结合配偶体神经配蛋白-1的tsA 201细胞之间形成的半突触。在使用缺乏胞外结构域的突变体neurexin-1 β的类似实验中，突触靶向的程度显著降低。此外，当α 4 β 2 AChR、α 7 AChR和neurexin-1 β在同一神经元中共表达时，只有α 4 β 2 AChR与neurexin-1 β在突触前末梢共定位。总的来说，这些数据表明neurexin-1 β将α 4 β 2 AChR靶向突触前末梢，其通过neurexin和神经配蛋白之间的跨突触相互作用而成熟。有趣的是，人类neurexin-1基因功能障碍与尼古丁依赖和自闭症谱系障碍有关。我们的研究结果提供了新的见解，可能的机制，功能失调neurexins，通过下游影响α 4 β 2乙酰胆碱受体，可能有助于这些神经系统疾病的病因。
The mechanisms involved in the targeting of neuronal nicotinic acetylcholine receptors (AChRs), critical for their functional organization at neuronal synapses, are not well understood. We have identified a novel functional association between alpha 4 beta 2 AChRs and the presynaptic cell adhesion molecule, neurexin-1 beta. In non-neuronal tsA 201 cells, recombinant neurexin-1 beta and mature alpha 4 beta 2 AChRs form complexes. alpha 4 beta 2 AChRs and neurexin-1 beta also coimmunoprecipitate from rat brain lysates. When exogenous alpha 4 beta 2 AChRs and neurexin-1 beta are coexpressed in hippocampal neurons, they are robustly targeted to hemi-synapses formed between these neurons and cocultured tsA 201 cells expressing neuroligin-1, a postsynaptic binding partner of neurexin-1 beta. The extent of synaptic targeting is significantly reduced in similar experiments using a mutant neurexin-1 beta lacking the extracellular domain. Additionally, when alpha 4 beta 2 AChRs, alpha 7 AChRs, and neurexin-1 beta are coexpressed in the same neuron, only the alpha 4 beta 2 AChR colocalizes with neurexin-1 beta at presynaptic terminals. Collectively, these data suggest that neurexin-1 beta targets alpha 4 beta 2 AChRs to presynaptic terminals, which mature by trans-synaptic interactions between neurexins and neuroligins. Interestingly, human neurexin-1 gene dysfunctions have been implicated in nicotine dependence and in autism spectrum disorders. Our results provide novel insights as to possible mechanisms by which dysfunctional neurexins, through downstream effects on alpha 4 beta 2 AChRs, may contribute to the etiology of these neurological disorders.