Mechanism and Function of Arc Palmitoylation

弧形棕榈酰化的机理和作用

• 批准号: 9223734
• 负责人: JOSEPH P ALBANESI
• 金额: $ 20.25万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9223734
• 关键词: AMPA Receptors; Acyltransferase; Adaptor Signaling Protein; Address; Affect; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Angelman Syndrome; Binding; Biochemical; Brain; Carbon; Cells; Cellular Membrane; Cognition Disorders; Cysteine; Data; Dendrites; Dendritic Spines; Dynamin 2; Electrophysiology (science); Elements; Endocytosis; Endosomes; Event; Excitatory Synapse; Fragile X Syndrome; Glutamate Receptor; Human; Immediate-Early Genes; Investigation; Learning; Link; Lipid Bilayers; Lipids; Location; Long-Term Depression; Long-Term Potentiation; Mediating; Membrane; Memory; Mental Retardation; Metabotropic Glutamate Receptors; Modeling; Modification; N-terminal; Nature; Neurons; Palmitates; Phospholipids; Phosphorylation; Predisposition; Process; Proteins; Proteolytic Processing; Regulation; Role; Schizophrenia; Substance abuse problem; Surface; Synapses; Synaptic plasticity; Testing; Translations; Tyrosine Phosphorylation; Work; amyloid precursor protein processing; clinically significant; density; experience; gene product; imaging approach; insight; mutant; notch protein; novel; palmitoylation; protein acyltransferase; public health relevance; receptor function; response; subcellular targeting; synaptic depression; thioester; trafficking; transcription factor

 DESCRIPTION (provided by applicant): Activity dependent changes in synaptic efficacy, such as those which occur during long-term potentiation (LTP) and long-term depression (LTD), are believed to underlie learning and memory. A key event in both LTP and LTD is the induction of a set of immediate-early gene products, including the activity-regulated cytoskeletal- associated protein (arc, also known as arg 3.1). The best characterized function of Arc is enhancement of the endocytic internalization of AMPA receptors in dendritic spines, a process associated with LTD. Arc has also been implicated in the proteolytic processing of amyloid precursor protein (APP) on the surface of endosomes. To mediate these activities, Arc must associate with cellular membranes, but the mechanism of its binding to membranes is not understood. In addressing this question, we found that Arc undergoes palmitoylation in neurons, allowing it to insert directly into the lipid bilayer. Unlike other forms of protein lipidation, palmitoylation is reversible and, hence, may be subject to conditional regulation. In Aim 1 of this project we propose to define the mechanism and biochemical consequences of Arc palmitoylation. We will determine if the level of Arc palmitoylation is responsive to LTP- and LTD-inducing paradigms, and we will identify which of the 23 known human forms of palmitoyl acyltransferase is (are) responsible for modifying Arc. Using a combination of biochemical and imaging approaches, we will determine how palmitoylation influences the subcellular distribution of Arc, its ability to self-assemble on the membranes of living cells, and its susceptibility to undergo tyrosine phosphorylation, another Arc modification identified in our studies. In Aim 2 we will carry out electrophysiological investigations aimed at understanding how Arc palmitoylation affects synaptic plasticity. Our previous work implicated Arc in the weakening of synaptic strength and the elimination of excitatory synapses. Preliminary data indicate that these effects may be mediated by Arc palmitoylation. Changes in Arc expression have been linked to numerous cognitive disorders, including mental retardation, Alzheimer's disease, and substance abuse. Therefore, elucidation of novel mechanisms of Arc regulation has potential clinical significance.

 描述（由申请人提供）：突触功效的活动依赖性变化，例如在长期增强（LTP）和长期抑制（LTD）期间发生的变化，被认为是学习和记忆中的关键事件的基础。 LTD 是一组立即早期基因产物的诱导，包括活性调节的细胞骨架相关蛋白（arc，也称为 arg 3.1）。树突棘中 AMPA 受体的内吞内化，与 LTD 相关的过程也涉及内体表面淀粉样前体蛋白 (APP) 的蛋白水解过程。为了介导这些活动，Arc 必须与细胞膜结合。其与膜结合的机制尚不清楚，在解决这个问题时，我们发现 Arc 在神经元中经历棕榈酰化，使其能够直接插入脂质双层中。脂化、棕榈酰化是可逆的，因此可能受到目标 1 的条件调节。 我们将确定 Arc 棕榈酰化的水平是否对 LTP 和 LTD 诱导范例有反应，并且我们将确定 23 种已知的人类形式的棕榈酰酰基转移酶中的哪一种是（是）负责修饰 Arc。通过结合生化和成像方法，我们将确定棕榈酰化如何影响 Arc 的亚细胞分布及其在活体细胞膜上自组装的能力。细胞及其对酪氨酸磷酸化的敏感性，这是我们研究中发现的另一种 Arc 修饰，在目标 2 中，我们将进行电生理学研究，以了解 Arc 棕榈酰化如何影响突触可塑性。初步数据表明，这些效应可能是由 Arc 棕榈酰化介导的，Arc 表达的变化与许多认知障碍有关。因此，阐明 Arc 调节的新机制具有潜在的临床意义。