Agrin gene expression

集聚蛋白基因表达

• 批准号: 7067567
• 负责人: MARTIN A SMITH
• 金额: $ 27.55万
• 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/7067567
• 关键词: RNA splicing; agrin; developmental neurobiology; electron microscopy; gene expression; gene mutation; glutamate receptor; hippocampus; immunocytochemistry; in situ hybridization; laboratory mouse; neurogenetics; neuromuscular junction; neurotransmitter receptor; polymerase chain reaction; protein binding; protein biosynthesis; protein structure function; protooncogene; receptor expression; synapses; synaptogenesis; tissue /cell culture

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）：集聚蛋白是一种细胞外基质蛋白，其引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积累。集聚蛋白也由中枢神经系统 (CNS) 中的神经元表达，但其功能尚不明确。例如，除了作为突触后组织者的作用外，集聚蛋白还参与调节轴突末端的分化以及轴突和树突的生长和分支。 作为了解中枢神经系统中集聚蛋白功能的另一种方法，我们重点关注确定集聚蛋白可能发挥作用的信号通路。这些研究最近发现了集聚蛋白的神经元受体，集中在神经元-神经元突触处，与介导集聚蛋白在肌肉中作用的肌肉特异性激酶复合物不同。集聚蛋白与该受体结合会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 和其他已知调节突触功能的激酶。在这里，我们提供了集聚蛋白受体是 100 kDa 膜酪氨酸激酶的证据。该受体的长期失活会导致神经元对兴奋性神经递质的反应减弱，这与钙稳态的改变相关。为了更多地了解集聚蛋白在大脑中的功能，我们将确定集聚蛋白受体的分子特性；表征调节其表达的细胞相互作用；检查抑制集聚蛋白受体表达的效果；确定集聚蛋白影响神经元对兴奋性刺激反应的机制。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。集聚蛋白是一种对神经肌肉连接至关重要的分子，是对兴奋性神经递质产生正常反应所必需的。根据我们之前的证明，集聚蛋白的表达是活动依赖性的，集聚蛋白可能被证明是大脑神经元活动的关键调节剂。因此，这些研究的结果可能与许多人类疾病的预防和治疗直接相关，例如癫痫症，这些疾病会破坏神经回路的行为。