Establishing Membrane Domains in Myelinated Nerve

描述（由申请人提供）：神经冲动在髓鞘神经中的快速传播取决于其在特殊膜域的分离。沿神经的髓鞘节段散布着无髓鞘的兰维耶结，其中含有钠离子通道簇，用于动作电位的再生。在淋巴结的两侧，分隔状连接将髓鞘末端环紧紧地连接到轴突膜上。这些旁结在物理上将淋巴结上的钠离子通道簇与髓鞘下方近旁阳极上的钾离子通道簇分开。控制髓磷脂中特殊膜结构域形成和维持的分子相互作用仍然知之甚少。我们已经确定了在CNS和PNS中，Contactin在分隔样旁神经连接形成中的重要作用（Boyle等人，2001；并在准备中）。接触蛋白与Caspr（接触蛋白相关蛋白）结合，这种相互作用对于Caspr运输到轴突膜是必要的，在轴突膜上，这种复合物参与连接粘附。然而，对于Contactin-Caspr复合物的表达如何在中枢和外周偏执狂中受到调节，人们知之甚少。我们已经确定了一种新的caspr相互作用蛋白，它可以调节caspr -接触蛋白复合物在神经元细胞表面的可用性和稳定性。目前还不清楚这种新蛋白在细胞内和完整神经系统中的分布和功能。本研究的目的是揭示这种新蛋白与Caspr的功能关联，并确定这种相互作用如何调节髓磷脂的组装和功能。这项工作将揭示对髓磷脂的发育和功能至关重要的蛋白质复合物的调控。了解控制髓鞘中蛋白复合物组装、拆卸和区室化定位的分子信号，将有助于设计旨在预防和恢复受脱髓鞘疾病影响的个体正常功能的策略。

DESCRIPTION (provided by applicant): The rapid propagation of nerve impulses in myelinated nerve depends on its segregation into specialized membrane domains. Myelin segments along the nerve are interspersed by the unmyelinated nodes of Ranvier that contain clusters of sodium channels and serve to regenerate the action potential. On both sides of the node, septate-like junctions tightly attach the terminal myelin loops to the axon membrane. These paranodal junctions physically segregate the sodium channel clusters at the node from potassium channel clusters at the juxtaparanode just underneath the myelin. The molecular interactions that control the formation and maintenance of specialized membrane domains in myelin remain poorly understood. We have established an important function for Contactin in the formation of the septate-like paranodal junctions in both the CNS and PNS (Boyle et al., 2001; and in preparation). Contactin associates with Caspr (Contactin-associated Protein) and this interaction is necessary for Caspr trafficking to the axon membrane where the complex engages in junctional adhesion. However, little is known about how the expression of the Contactin-Caspr complex is regulated at central and peripheral paranodes. We have identified a novel Caspr-interacting protein that may regulate the availability and stability of the Caspr-Contactin complex on neuronal cell surfaces. Nothing is currently known about the distribution and function of this novel protein within cells and in the intact nervous system. The goal of this proposal is to reveal the functional association of this novel protein with Caspr and determine how this interaction regulates myelin assembly and function. This work will shed new light on the regulation of a protein complex that is vital for the development and function of myelin. Understanding the molecular signals that control the assembly, disassembly and compartmentalized localization of protein complexes in myelin will help in the design of strategies aimed at preventing and restoring proper functions in individuals affected by demyelinating diseases.