Establishing Membrane Domains in Myelinated Nerve

描述(申请人提供)：神经冲动在有髓神经中的快速传播依赖于它被分离到专门的膜域。沿着神经的髓鞘节段被兰维尔的无髓鞘结节点缀，这些无髓鞘结节含有成簇的钠通道，用于再生动作电位。在结节的两侧，分隔状连接将终末髓鞘环紧密地附着在轴突膜上。这些旁结节连接在物理上将节点上的钠通道簇与紧靠髓鞘下的旁阳极上的钾通道簇分开。控制髓鞘中特殊膜域的形成和维持的分子相互作用仍然知之甚少。我们已经确立了Contactin在CNS和PNS中隔状旁结节连接形成中的重要作用(Boyle等人，2001；以及准备中)。Contactin与CASPR(Contactin-Associated Protein)结合，这种相互作用是CASPR转运到轴突膜上所必需的，在轴突膜上，复合体参与连接黏附。然而，对于Contactin-CASPR复合体在中枢和外周副神经节的表达是如何调节的，我们知之甚少。我们已经确定了一种新的CASPR相互作用蛋白，它可能调节神经细胞表面CASPR-Contactin复合体的可用性和稳定性。目前还不知道这种新的蛋白质在细胞和完整的神经系统中的分布和功能。这项建议的目的是揭示这种新的蛋白质与CASPR的功能联系，并确定这种相互作用如何调节髓鞘的组装和功能。这项工作将为调节一种对髓鞘的发育和功能至关重要的蛋白质复合体提供新的线索。了解控制髓鞘中蛋白质复合体组装、分解和区隔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的适当功能的策略。

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.