DEG/ENaC Ion Channels in the Function of the Nervous System: From Worm to Man.
DEG/ENaC Ion Channels in the Function of the Nervous System: From Worm to Man.
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DOI：
10.1007/978-981-16-4254-8_9
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发表时间：
2021-01-01
影响因子：
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通讯作者：
Bianchi, Laura
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作者：
Bianchi, Laura
DEG/ENaC通道是电压无关的Na+/Ca2+通道，在物种中保守，在许多不同的细胞类型和组织中表达，在那里它们有助于广泛的生理功能，从经上皮Na+运输，到感觉知觉，学习和记忆。在本章中，我们将重点介绍在神经系统中表达的这个家族的成员，并根据它们的功能对它们进行分组。在结构上，DEG/ENaC通道是由相同或同源亚基形成的三聚体，每个亚基都像紧握的手一样从质膜伸出来。对鸡ASIC1a在关闭、失活和打开状态下的晶体学研究揭示了这些通道的门控和渗透特性的重要细节，总的来说，它们表明通道的细胞外结构域在门控过程中发生了很大的构象变化。绝大多数通道的胞外结构域在不同的成员和物种中是保守的；然而，包括在手指和手掌附近插入额外环路在内的关键变化最有可能赋予门控特异性。事实上，由于DEG/ENaC通道具有广泛的生理功能，它们可以受到多种刺激的门控，包括机械力、质子和肽。有趣的是，DEG/ENaC通道不仅在神经元中表达，也在胶质细胞中表达。对秀丽隐杆线虫的研究现在开始揭示神经胶质DEG/ENaC在神经系统功能中的作用，并表明它们可能与控制细胞外微环境中的离子浓度有关。最后，当DEG/ENaC通道因基因突变或长期酸中毒而过度激活时，它们可能变得有毒并导致神经元死亡，从而导致中风和缺血时神经元死亡。综上所述，对不同物种神经系统中表达的DEG/ENaC通道的分子、结构和行为研究突出了这些通道在神经元功能中的关键作用。这些数据使DEG/ENaC通道处于一个极佳的位置，被认为是治疗从疼痛到癫痫和缺血等几种神经系统疾病和疾病的药物靶点。
DEG/ENaC channels are voltage-independent Na+/Ca2+ channels that are conserved across species and are expressed in many different cell types and tissues, where they contribute to a wide array of physiological functions from transepithelial Na+ transport, to sensory perception, and learning and memory. In this chapter, we focus on the members of this family that are expressed in the nervous system, grouping them based on their function. Structurally, DEG/ENaC channels are trimers formed by either identical or homologous subunits, each one protruding from the plasma membrane like a clenched hand. Crystallographic studies on chicken ASIC1a in the closed, inactivated, and open states revealed important details about the gating and permeation properties of these channels, and overall they show that the extracellular domain of the channel undergoes large conformational changes during gating. The vast majority of the channel's extracellular domain is conserved across different members and species; however, key changes including the insertion of extra loops near the finger and palm domains most likely confers gating specificity. Indeed, DEG/ENaC channels are gated by a wide range of stimuli, including mechanical forces, protons, and peptides, owing to the wide array of physiological functions they serve. Interestingly, DEG/ENaC channels are not only expressed in neurons but also in glia. Work in C. elegans is now beginning to shed new light on the role of glial DEG/ENaC in the function of the nervous system and suggests that they may be implicated in controlling ionic concentrations in the extracellular microenvironment. Finally, DEG/ENaC channels can become toxic and cause neuronal death when they are hyperactivated by genetic mutations or prolonged acidosis causing them to contribute to neuronal demise in stroke and ischemia. Taken together, molecular, structural, and behavioral work on DEG/ENaC channels expressed in the nervous system of different species highlights the crucial role of these channels in neuronal function. These data place DEG/ENaC channels in an excellent position for being considered as drug targets for the treatment of several neurological conditions and disorders from pain to epilepsy and ischemia.