Agrin gene expression

集聚蛋白基因表达

• 批准号: 7448471
• 负责人: MARTIN A SMITH
• 金额: $ 26.75万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7448471
• 关键词: Affinity; Agrin; Axon; Behavior; Behavior Control; Binding; Biochemical; Brain; Calcium; Calmodulin; Cell Surface Proteins; Cell Surface Receptors; Cholinergic Receptors; Chromosome Pairing; Chronic; Cloning; Complement; Complex; Dendrites; Dependence; Development; Disease; Epilepsy; Exhibits; Extracellular Matrix Proteins; Gene Expression; Growth; Homeostasis; Human; Image; In Vitro; Knowledge; Learning; Ligands; Light; Maintenance; Mass Spectrum Analysis; Mediating; Membrane; Molecular; Motor Neurons; Mus; Muscle; Muscle-Specific Kinase; Mutant Strains Mice; Neuraxis; Neuromuscular Junction; Neurons; Neurotransmitters; Numbers; Pattern; Perinatal; Phenotype; Phosphotransferases; Physiological; Presynaptic Terminals; Prevention; Property; Protein Isoforms; Protein Tyrosine Kinase; Proteins; RNA Interference; Research Personnel; Role; Shapes; Signal Pathway; Son; Stimulus; Surface; Synapses; Work; agrin receptor; calmodulin-dependent protein kinase II; in vivo; knockout gene; mutant; neural circuit; neuronal excitability; postsynaptic; programs; receptor; receptor expression; research study; response; synaptic function

DESCRIPTION (provided by applicant): Agrin is an extracellular matrix protein that directs the accumulation of acetylcholine receptors in the postsynaptic apparatus of the developing neuromuscular junction. Agrin is also expressed by neurons in the central nervous system (CNS), but its function is less well defined. For example, in addition to a role as a postsynaptic organizer, agrin has also been implicated in regulating the differentiation of axon terminals as well as growth and branching of axons and dendrites. As an alternate approach to understanding agrin function in the CNS, we have focused on identifying signal pathways through which agrin might act. These studies recently discovered a neuronal receptor for agrin, concentrated at neuron-neuron synapses, and distinct from the muscle specific kinase complex that mediates agrin's action in muscle. Agrin binding to this receptor triggers a rapid increase in intracellular calcium and activates calcium/calmodulin-dependent kinase II and other kinases known to regulate synaptic function. Here we provide evidence the agrin receptor is a 100 kDa membrane tyrosine kinase. Chronic inactivity of this receptor results in decreased neuronal responses to excitatory neurotransmitters, correlated with alterations in calcium homeostasis. To learn more about agrin's function in brain, we will establish the molecular identity of the agrin receptor; characterize the cellular interactions that regulate its expression; examine the effects of suppressing agrin receptor expression and; identify mechanisms by which agrin influences neuronal responses to excitatory stimuli. The experiments outlined here are aimed at understanding the cellular mechanisms that control behavior of neural circuits in brain. Agrin, a molecule critical for neuromuscular connectivity, is required for development of normal responses to excitatory neurotransmitters. In light of our earlier demonstration that expression of agrin is activity dependent, agrin may prove to be a key modulator of neuronal activity in brain. The results of these studies, therefore, are likely to be directly relevant to the prevention and treatment of a number of human disorders, such as epilepsy, that disrupt behavior of neural circuits.

描述（由申请人提供）：聚集蛋白是一种细胞外基质蛋白，其指导乙酰胆碱受体在发育中的神经肌肉接头的突触后装置中的积累。聚集蛋白也由中枢神经系统（CNS）中的神经元表达，但其功能不太清楚。例如，除了作为突触后组织者的作用之外，聚集蛋白还涉及调节轴突终末的分化以及轴突和树突的生长和分支。 作为了解聚集蛋白在中枢神经系统中功能的另一种方法，我们专注于识别聚集蛋白可能起作用的信号通路。这些研究最近发现了聚集蛋白的神经元受体，集中在神经元-神经元突触处，并且不同于介导聚集蛋白在肌肉中的作用的肌肉特异性激酶复合物。聚集蛋白与该受体的结合引发细胞内钙的快速增加，并激活钙/钙调蛋白依赖性激酶II和已知调节突触功能的其他激酶。在这里，我们提供的证据聚集蛋白受体是一个100 kDa的膜酪氨酸激酶。这种受体的慢性失活导致神经元对兴奋性神经递质的反应降低，与钙稳态的改变相关。要了解更多关于聚集蛋白在大脑中的功能，我们将建立聚集蛋白受体的分子身份;表征调节其表达的细胞相互作用;检查抑制聚集蛋白受体表达的影响;确定聚集蛋白影响神经元对兴奋性刺激的反应的机制。这里概述的实验旨在了解控制大脑神经回路行为的细胞机制。聚集蛋白是神经肌肉连接的关键分子，对兴奋性神经递质的正常反应的发展是必需的。鉴于我们先前的研究表明聚集蛋白的表达是活动依赖性的，聚集蛋白可能被证明是脑中神经元活动的关键调节剂。因此，这些研究的结果可能与预防和治疗一些人类疾病直接相关，例如癫痫，这些疾病会破坏神经回路的行为。