Regulation of splicing in a model voltage-gated Na+ channel

电压门控Na通道模型中剪接的调节

• 批准号: BB/J005002/1
• 负责人: Richard Baines
• 金额: $ 53.67万
• 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: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ005002%2F1
• 关键词: Regulation; splicing; model; voltage; gated

The mammalian central nervous system is composed of a multitude of nerve cell types. These cell types differ in the targets 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). The ability to fire action potentials is due to the presence of a variety of ion channels in the neuronal membrane. These proteins are encoded by genes, but we now know that the diversity of ion channel types present in the nervous system far exceeds the number of genes that encode for them. This increased diversity is due, in greater part, to a process termed alternative splicing. Essentially genes are composed of coding regions termed exons that are separated by non-coding regions called introns. When genes are expressed the initial transcript produced (called a pre-mRNA) contains both introns and exons. The first step on the road to making protein is to splice out (i.e. remove) the introns to produce a continuous coding sequence. However, we now know that in addition to introns, some exons can also be spliced out. This results in coding sequences that can differ and that in turn produce related, but similarly different proteins that ultimately form ion channels that have different functional properties. Thus, one gene can in fact encode many related proteins due to the existence of alternative splicing. Although the mechanics of splicing are quite well understood, how individual nerve cells 'decide' how to splice specific pre-mRNA transcripts remains unknown.

哺乳动物的中枢神经系统由多种神经细胞类型组成。这些细胞类型在它们接触的目标，它们释放的信号化学物质（神经递质）以及它们能够激发触发神经递质释放的电动作电位的方式方面有所不同。激发动作电位的能力是由于神经元膜中存在多种离子通道。这些蛋白质由基因编码，但我们现在知道，神经系统中存在的离子通道类型的多样性远远超过了编码它们的基因数量。这种多样性的增加在很大程度上是由于一种称为选择性剪接的过程。基因基本上由称为外显子的编码区组成，外显子被称为内含子的非编码区隔开。当基因表达时，产生的初始转录物（称为前mRNA）包含内含子和外显子。制造蛋白质的第一步是剪接掉（即移除）内含子以产生连续的编码序列。然而，我们现在知道，除了内含子，一些外显子也可以被剪接出来。这导致编码序列可以不同，进而产生相关但类似不同的蛋白质，最终形成具有不同功能特性的离子通道。因此，由于选择性剪接的存在，一个基因实际上可以编码许多相关蛋白。虽然剪接的机制已经被很好地理解，但是个体神经细胞如何“决定”如何剪接特定的前mRNA转录本仍然是未知的。

项目成果

Seizure suppression through manipulating splicing of a voltage-gated sodium channel.

• DOI: 10.1093/brain/awv012
• 发表时间: 2015-04
• 期刊: Brain : a journal of neurology
• 作者: Lin WH;He M;Baines RA
• 通讯作者: Baines RA

The ADAR RNA editing enzyme controls neuronal excitability in Drosophila melanogaster.

• DOI: 10.1093/nar/gkt909
• 发表时间: 2014-01
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Li X;Overton IM;Baines RA;Keegan LP;O'Connell MA
• 通讯作者: O'Connell MA

Seizure control through genetic and pharmacological manipulation of Pumilio in Drosophila: a key component of neuronal homeostasis.

• DOI: 10.1242/dmm.027045
• 发表时间: 2017-02-01
• 期刊: Disease models & mechanisms
• 影响因子: 4.3
• 作者: Lin WH;Giachello CN;Baines RA
• 通讯作者: Baines RA

Regulation of membrane excitability: a convergence on voltage-gated sodium conductance.

• DOI: 10.1007/s12035-014-8674-0
• 发表时间: 2015-02
• 期刊: MOLECULAR NEUROBIOLOGY
• 影响因子: 5.1
• 作者: Lin, Wei-Hsiang;Baines, Richard A.
• 通讯作者: Baines, Richard A.