Stoichiometry for activation of neuronal α7 nicotinic receptors
Stoichiometry for activation of neuronal α7 nicotinic receptors
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DOI：
10.1073/pnas.1315775110
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发表时间：
2013-12-17
影响因子：
11.1
通讯作者：
Bouzat, Cecilia
中科院分区：
文献类型：
--
作者：
Andersen, Natalia;Corradi, Jeremias;Bouzat, Cecilia
神经元α - 7烟碱受体对乙酰胆碱（ACh）或其水解产物胆碱的反应引起快速阳离子内流。它们有助于认知、突触可塑性和神经保护，并与神经退行性疾病和神经精神疾病有关。然而，α 7通常定位于远端神经释放乙酰胆碱的位点，并以低亲和力结合乙酰胆碱，从而引发其生物反应，并以低激动剂占用率。为了评估当ACh占据少于5个相同结合位点时α 7的功能，我们测量了5个ACh结合位点中的4个被禁用的单个受体的开放通道寿命。为了提高固有的短暂alpha 7通道打开的时间分辨率，使用背景突变或增强器来增加打开持续时间。我们发现，在只有一个完整结合位点的受体中，开放通道寿命与具有五个完整结合位点的受体没有区别，这与原型神经递质门控离子通道的预期相反，其中开放通道寿命随着激动剂占据的结合位点的数量而增加。用相关的5-HT(3)A受体取代α 7的膜嵌入结构域增加了需要占据的位点数量，以实现最大的开放通道寿命，从而揭示了这些受体的检测器和致动器结构域之间独特的相互依存关系。单次占用引发完整生物反应的独特能力使α - 7适应于体积传递，这是神经系统和非神经元细胞中乙酰胆碱介导的信号传导的普遍机制。
Neuronal alpha 7 nicotinic receptors elicit rapid cation influx in response to acetylcholine (ACh) or its hydrolysis product choline. They contribute to cognition, synaptic plasticity, and neuroprotection and have been implicated in neurodegenerative and neuropsychiatric disorders. alpha 7, however, often localizes distal to sites of nerve-released ACh and binds ACh with low affinity, and thus elicits its biological response with low agonist occupancy. To assess the function of alpha 7 when ACh occupies fewer than five of its identical binding sites, we measured the open-channel lifetime of individual receptors in which four of the five ACh binding sites were disabled. To improve the time resolution of the inherently brief alpha 7 channel openings, background mutations or a potentiator was used to increase open duration. We find that, in receptors with only one intact binding site, the open-channel lifetime is indistinguishable from receptors with five intact binding sites, counter to expectations from prototypical neurotransmitter-gated ion channels where the open-channel lifetime increases with the number of binding sites occupied by agonist. Replacing the membrane-embedded domain of alpha 7 by that of the related 5-HT(3)A receptor increases the number of sites that need to be occupied to achieve the maximal open-channel lifetime, thus revealing a unique interdependence between the detector and actuator domains of these receptors. The distinctive ability of a single occupancy to elicit a full biological response adapts alpha 7 to volume transmission, a prevalent mechanism of ACh-mediated signaling in the nervous system and nonneuronal cells.