The Dynamics of Synaptic Component at the Neuromuscular Junction of Living Animal

活体动物神经肌肉接头处突触成分的动力学

基本信息

批准号：
8462696
负责人：
MOHAMMED AKAABOUNE
金额：
$ 31万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8462696
关键词：
Adaptor Signaling Protein Address Adult Animals Back Biological Models Cell membrane Cells Cholinergic Receptors Data Depressed mood Development Disease Dystrophin Electroporation Exhibits Gene Mutation Glycoproteins Goals Health Human Image Label Laboratories Lateral Lead Length Life Link Lysosomes Maintenance Membrane Metabolic Molecular Monitor Motor Neurons Movement Mus Muscle Muscle Fibers Mutant Strains Mice Mutation Nerve Neuraxis Neuromuscular Diseases Neuromuscular Junction Neuromuscular Junction Diseases Neurotransmitter Receptor Neurotransmitters Nicotinic Receptors Pathway interactions Pattern Peripheral Phenotype Plasmids Play Postsynaptic Membrane Process Property Proteins Recovery Recycling Regulation Role Shapes Signaling Protein Staging Sternocleidomastoid Muscle Structure Study models Synapses Synaptic Membranes Synaptic Receptors Synaptic Transmission Synaptic plasticity System Testing Time Work alpha-dystrobrevin base cholinergic synapse density effective intervention effective therapy in vivo insight neurotransmission postnatal postsynaptic pup receptor receptor density receptor recycling research study scaffold skeletal synaptic function synaptogenesis syntrophin alpha1 tool trafficking

项目摘要

PROJECT SUMMARY Our long term goal is to better understand how neurotransmitter receptor density is maintained and regulated at mature and developing synapses in vivo. We are using the neuromuscular junction (NMJ), an excitatory cholinergic synapse between motor neurons and muscle fibers as our model system, because of the significant impact on human health of disorders at this synapse and because it provides the most accessible model system to study the process of neurotransmitter receptor recycling in vivo. Until recently receptor recycling was thought to be an exclusive property of neurotransmitter receptors in the central nervous system, but we discovered that significant numbers of acetylcholine receptors (AChRs) are recycled back onto the postsynaptic membrane after internalization, contributing to the maintenance of the postsynaptic density of receptors at mature synapses. We will pursue two goals to assess potential roles for recycling during synaptic development and in maturity and two goals to test the roles of molecules that are strong candidates for participation in the recycling process. We have focused on the roles of alpha-dystrobrevin and alpha-syntrophin in regulating the recycling of AChR onto the postsynaptic membrane because mutations in these proteins are clearly associated with human disorders of neuromuscular transmission, and mutations of these genes in mice have been demonstrated to dramatically alter the number of AChR at mature synapses, as might be expected if receptor recycling was aberrant. Understanding the molecular basis of receptor recycling could lead to more effective intervention and therapy that could increase synaptic transmission by increasing AChR number or density in neuromuscular diseases. Furthermore, it seems likely that some aspects of receptor recycling will be common to all cells, so we expect that these results will be useful not only in understanding the development of the neuromuscular junction, but will provide insights into the long-term role of receptor recycling in synaptogenesis and synaptic plasticity at less accessible central synapses.

项目摘要我们的长期目标是更好地了解如何保持神经递质受体密度并在体内成熟并发展突触。我们正在使用神经肌肉连接（NMJ），运动神经元和肌肉纤维之间的兴奋性胆碱能突触我们的模型系统，因为这对疾病的人类健康产生了重大影响突触，因为它提供了最容易访问的模型系统来研究神经递质受体在体内回收。直到最近，受体回收被认为是中枢神经系统中神经递质受体的独家特性，但我们发现大量乙酰胆碱受体（ACHR）被回收回到内在化后的突触后膜，有助于维持成熟突触处受体的突触后密度。我们将追求两个目标来评估在突触发展和成熟度中回收的潜在作用，以及两个目标测试的目标参与回收过程的有力候选者的分子的作用。我们有专注于α-脱节型和α-链霉素在调节回收中的作用 ACHR到突触后膜上，因为这些蛋白质中的突变显然是与神经肌肉传播的人类疾病以及这些基因的突变有关在小鼠中，已证明在成熟突触时大大改变了ACHR的数量，如果受体回收是异常的，则可以预期。了解分子基础受体回收可能会导致更有效的干预和治疗，从而增加通过增加神经肌肉疾病的ACHR数量或密度来增加突触传播。此外，似乎所有细胞的受体回收的某些方面都可能是共同的因此，我们期望这些结果不仅有用神经肌肉连接，但将提供有关受体回收的长期作用的见解突触发生和突触可塑性在较低的中央突触下。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Recycling of acetylcholine receptors at ectopic postsynaptic clusters induced by exogenous agrin in living rats.

DOI：
10.1016/j.ydbio.2014.07.018
发表时间：
2014-10-01
期刊：
DEVELOPMENTAL BIOLOGY
影响因子：
2.7
作者：
Brenner, Hans Rudolf;Akaaboune, Mohammed
通讯作者：
Akaaboune, Mohammed

Phosphorylation of α-dystrobrevin is essential for αkap accumulation and acetylcholine receptor stability.

α-dystrobrevin 的磷酸化对于 αkap 积累和乙酰胆碱受体稳定性至关重要。

DOI：
10.1074/jbc.ra120.013952
发表时间：
2020
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Chen,Po-Ju;Zelada,Diego;Belhasan,DinaCheryne;Akaaboune,Mohammed
通讯作者：
Akaaboune,Mohammed

Acetylcholinesterase mobility and stability at the neuromuscular junction of living mice.

活体小鼠神经肌肉接头处乙酰胆碱酯酶的流动性和稳定性。

DOI：
10.1091/mbc.e07-02-0093
发表时间：
2007
期刊：
Molecular biology of the cell
影响因子：
3.3
作者：
Martinez-PenayValenzuela,Isabel;Akaaboune,Mohammed
通讯作者：
Akaaboune,Mohammed

A role for the calmodulin kinase II-related anchoring protein (αkap) in maintaining the stability of nicotinic acetylcholine receptors.

DOI：
10.1523/jneurosci.6477-11.2012
发表时间：
2012-04-11
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Mouslim C;Aittaleb M;Hume RI;Akaaboune M
通讯作者：
Akaaboune M

Calcium/calmodulin kinase II-dependent acetylcholine receptor cycling at the mammalian neuromuscular junction in vivo.

DOI：
10.1523/jneurosci.3309-10.2010
发表时间：
2010-09-15
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Martinez-Pena y Valenzuela I;Mouslim C;Akaaboune M
通讯作者：
Akaaboune M