Regulation of Arp2/3-mediated actin polymerisation by PICK1 in neuronal function

PICK1 对神经元功能中 Arp2/3 介导的肌动蛋白聚合的调节

• 批准号: BB/H014284/1
• 负责人: Jonathan Hanley
• 金额: $ 64.19万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH014284%2F1
• 关键词: Regulation; Arp2; mediated; actin; polymerisation

Nerve cells (neurons) in the brain communicate with one another at connections called synapses. A chemical (neurotransmitter) is released from a neuron and travels across the synapse to activate receptors in the adjacent neuron. Synapses can change their strength (known as 'synaptic plasticity') by altering the number of receptors found on the surface of the neuron in the synapse. This process is thought to underlie learning and memory, because the memory is likely to be stored in a circuit of interconnected neurons. An important mechanism for moving receptors around neurons involves a protein called actin, which forms filaments that shrink and grow to physically manoeuvre parts of the cell or its constituents. We have found that a protein (called PICK1) is involved in controlling the formation of these actin filaments, and in this way controls the movement of neurotransmitter receptors to or from the synapse. Individual neurons are constituents of neuronal circuits that control complex behaviour or memory systems, and these neurons receive various inputs that trigger biochemical reactions inside them. These biochemical reactions can influence countless different processes in cells, and we propose that PICK1's regulation of actin could be controlled in this way. Therefore, in the proposed research, we aim to investigate how PICK1 is 'switched on' or 'switched off' with respect to its control of actin filaments. We are going to investigate three types of biochemical reaction in this work, all of which are specific varieties of well-known cellular mechanisms. We will initially carry out experiments on protein molecules in test-tubes to study the biochemical processes, and then do experiments in living neurons cultured in vitro to investigate how manipulating these biochemical reactions affects synaptic plasticity. We will use two approaches to study synaptic plasticity in neurons. First, we will visualise the movement of neurotransmitter receptors using microscopy, and second, we will analyse the activity of neurons by recording their electrical activity. This work is important because it will lead to a wealth of new information about synaptic plasticity, and hence learning and memory mechanisms. The movement of neurotransmitter receptors to and from the synapse is thought to underlie the altered neuronal activity in several brain diseases, such as stroke, Alzheimer's, and also in drug addiction. Therefore, the mechanisms that we will study in this research will add to our knowledge about these debilitating diseases, and may contribute to developing therapies. In addition, the control of actin is absolutely essential to numerous processes in all of the cells in our bodies, not just neurons. Therefore, this work will provide important information that will enhance the study of many other cellular processes and disease mechanisms.

大脑中的神经细胞（神经元）通过称为突触的连接相互交流。一种化学物质（神经递质）从神经元中释放出来，穿过突触激活相邻神经元中的受体。突触可以通过改变突触中神经元表面受体的数量来改变其强度（称为“突触可塑性”）。这个过程被认为是学习和记忆的基础，因为记忆可能存储在相互连接的神经元回路中。在神经元周围移动受体的一个重要机制涉及一种称为肌动蛋白的蛋白质，它形成收缩和生长的细丝，以物理方式操纵细胞或其成分的部分。我们发现一种蛋白质（称为PICK1）参与控制这些肌动蛋白丝的形成，并以这种方式控制神经递质受体进出突触的运动。单个神经元是控制复杂行为或记忆系统的神经元回路的组成部分，这些神经元接收各种输入，触发它们内部的生化反应。这些生化反应可以影响细胞中无数不同的过程，我们认为PICK1对肌动蛋白的调节可以通过这种方式来控制。因此，在拟议的研究中，我们的目标是调查如何PICK1是“打开”或“关闭”相对于其控制的肌动蛋白丝。在这项工作中，我们将研究三种类型的生化反应，所有这些都是众所周知的细胞机制的特定品种。我们将首先在试管中对蛋白质分子进行实验，以研究生化过程，然后在体外培养的活神经元中进行实验，以研究操纵这些生化反应如何影响突触可塑性。我们将使用两种方法来研究神经元中的突触可塑性。首先，我们将使用显微镜观察神经递质受体的运动，其次，我们将通过记录神经元的电活动来分析神经元的活动。这项工作很重要，因为它将导致大量关于突触可塑性的新信息，从而学习和记忆机制。神经递质受体往返于突触的运动被认为是几种脑部疾病中神经元活动改变的基础，如中风，阿尔茨海默氏症，以及药物成瘾。因此，我们将在这项研究中研究的机制将增加我们对这些衰弱性疾病的了解，并可能有助于开发治疗方法。此外，肌动蛋白的控制对于我们身体中所有细胞的许多过程都是绝对必要的，而不仅仅是神经元。因此，这项工作将提供重要的信息，将加强许多其他细胞过程和疾病机制的研究。

项目成果

Cortactin regulates endo-lysosomal sorting of AMPARs via direct interaction with GluA2 subunit.

• DOI: 10.1038/s41598-018-22542-z
• 发表时间: 2018-03-07
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Parkinson GT;Chamberlain SEL;Jaafari N;Turvey M;Mellor JR;Hanley JG
• 通讯作者: Hanley JG

PICK1 links AMPA receptor stimulation to Cdc42.

• DOI: 10.1016/j.neulet.2014.11.046
• 发表时间: 2015-01-12
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Rocca DL;Hanley JG
• 通讯作者: Hanley JG

PICK1 links Argonaute 2 to endosomes in neuronal dendrites and regulates miRNA activity.

• DOI: 10.1002/embr.201337631
• 发表时间: 2014-05
• 期刊: EMBO REPORTS
• 影响因子: 7.7
• 作者: Antoniou, Anna;Baptista, Marcio;Carney, Nicholas;Hanley, Jonathan G.
• 通讯作者: Hanley, Jonathan G.

Actin-dependent mechanisms in AMPA receptor trafficking.

• DOI: 10.3389/fncel.2014.00381
• 发表时间: 2014
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3
• 作者: Hanley JG

The small GTPase Arf1 modulates Arp2/3-mediated actin polymerization via PICK1 to regulate synaptic plasticity.

• DOI: 10.1016/j.neuron.2013.05.003
• 发表时间: 2013-07-24
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Rocca DL;Amici M;Antoniou A;Blanco Suarez E;Halemani N;Murk K;McGarvey J;Jaafari N;Mellor JR;Collingridge GL;Hanley JG
• 通讯作者: Hanley JG