How does alternate splicing of a sodium channel gene generate diversity in neuronal signalling?

钠通道基因的交替剪接如何产生神经元信号传导的多样性？

• 批准号: BB/G005885/1
• 负责人: Richard Baines
• 金额: $ 50.85万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FG005885%2F1
• 关键词: How; does; alternate; splicing; sodium

The human brain contains a staggeringly large number of nerve cells (neurons) that form networks of connections (synapses) with one another. These neuronal circuits control almost everything we do, including behaviours such as breathing, walking and learning. Diversity of behaviour is mirrored by the need for a similar degree of diversity of function of individual nerve cells. Thus, neurons differ in the target that they contact, the signalling chemicals (neurotransmitters) they release, and the way in which they are able to fire electrical action potentials that trigger release of their neurotransmitter(s). Indeed, the degree of diversity of these characteristics is likely orders of magnitude greater than the number of genes present in the genome and, as such, additional mechanisms are required. Recent research suggests that additional diversity is due, at least in part, to different protein products being produced from the same genes. Alternate splicing, as this is called, results in multiple related proteins being encoded within one gene. Each protein variant produced has the capability of conferring different properties to the neuron in which expression occurs. Although now established, it remains largely to be shown how splicing induces changes to neuron function. We use the fruitfly because it is very amenable to genetic analysis, the complete genome has been sequenced, and because it provides a simple model of the human nervous system. Our study will inform us how our own nerve cells are able to develop to have different properties from one another.

人脑包含数量惊人的神经细胞（神经元），它们相互形成连接网络（突触）。这些神经元回路几乎控制着我们所做的一切，包括呼吸、行走和学习等行为。行为的多样性反映在个体神经细胞功能相似程度的多样性的需要上。因此，神经元在它们接触的目标、它们释放的信号化学物质（神经递质）以及它们能够激发电动作电位以触发神经递质释放的方式方面有所不同。事实上，这些特征的多样性程度可能比基因组中存在的基因数量大几个数量级，因此需要额外的机制。最近的研究表明，额外的多样性至少部分归因于相同基因产生的不同蛋白质产物。所谓的交替剪接，会导致一个基因内编码多种相关蛋白质。产生的每种蛋白质变体都能够赋予发生表达的神经元不同的特性。尽管现已确定，但剪接如何引起神经元功能的变化仍有待进一步研究。我们使用果蝇是因为它非常适合遗传分析，完整的基因组已被测序，并且因为它提供了人类神经系统的简单模型。我们的研究将告诉我们我们自己的神经细胞如何能够发展为具有彼此不同的特性。

项目成果

Activity-dependent alternative splicing increases persistent sodium current and promotes seizure.

• DOI: 10.1523/jneurosci.6042-11.2012
• 发表时间: 2012-05-23
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Lin WH;Günay C;Marley R;Prinz AA;Baines RA
• 通讯作者: Baines RA

The effects of knock-down resistance mutations and alternative splicing on voltage-gated sodium channels in Musca domestica and Drosophila melanogaster.

• DOI: 10.1016/j.ibmb.2020.103388
• 发表时间: 2020-05
• 期刊: Insect biochemistry and molecular biology
• 影响因子: 3.8
• 作者: A. J. Thompson;Paul S Verdin;M. Burton;T. Davies;M. Williamson;L. Field;R. Baines;I. Mellor;I. Duce