Agrin gene expression

描述(由申请人提供)：AGRIN是一种细胞外基质蛋白，它引导乙酰胆碱受体在发育中的神经肌肉连接的突触后装置中积累。AGRIN也由中枢神经系统(CNS)的神经元表达，但其功能还不是很清楚。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终末的分化以及轴突和树突的生长和分支。作为了解集聚蛋白在中枢神经系统中功能的另一种方法，我们将重点放在识别集聚蛋白可能发挥作用的信号通路上。这些研究最近发现了一种集聚蛋白的神经元受体，集中在神经元-神经元突触上，与肌肉中介导集聚蛋白作用的肌肉特异性激酶复合体不同。与这种受体结合后，细胞内钙离子迅速增加，并激活钙/钙调蛋白依赖的激酶II和其他已知的调节突触功能的激酶。在这里，我们提供了集聚蛋白受体是一个100 kDa的膜酪氨酸激酶的证据。这种受体的慢性不活跃会导致神经元对兴奋性神经递质的反应减弱，这与钙稳态的改变有关。为了更多地了解集聚蛋白在大脑中的功能，我们将建立集聚蛋白受体的分子同一性；表征调节集聚蛋白受体表达的细胞相互作用；研究抑制集聚蛋白受体表达的效果；以及确定集聚蛋白影响神经元对兴奋刺激的反应的机制。这里概述的实验旨在了解控制大脑中神经回路行为的细胞机制。Agin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的正常反应所必需的。鉴于我们早期证明集聚蛋白的表达是活性依赖的，集聚蛋白可能被证明是大脑中神经元活动的关键调节器。因此，这些研究的结果很可能与一些人类疾病的预防和治疗直接相关，例如癫痫，这些疾病扰乱了神经回路的行为。

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.