Establishing Membrane Domains in Myelinated Nerve

描述（由申请人提供）：神经冲动在有髓鞘神经中的快速传播取决于其分离成专门的膜域。沿神经的髓鞘段沿着散布有无髓鞘的兰氏结，其含有钠通道簇并用于再生动作电位。在淋巴结的两侧，隔样连接将终末髓鞘环紧密地连接到轴突膜上。这些结旁连接将结处的钠离子通道簇与髓鞘下方的结旁连接处的钾离子通道簇物理隔离。控制髓鞘中专门的膜结构域的形成和维持的分子相互作用仍然知之甚少。我们已经确定了Contactin在CNS和PNS中形成隔样结旁连接中的重要功能（波义耳et al.，2001年;并在筹备中）。接触蛋白与Caspr（接触蛋白相关蛋白）相关联，并且这种相互作用对于Caspr运输到轴突膜是必需的，在轴突膜中复合物参与连接粘附。然而，很少有人知道如何表达的接触蛋白-Caspr复合物是在中央和周边paranode调节。我们已经确定了一种新的Caspr-interacting蛋白，可以调节神经元细胞表面Caspr-Contactin复合物的可用性和稳定性。目前还不知道这种新蛋白在细胞内和完整神经系统中的分布和功能。该提案的目标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鞘组装和功能。这项工作将为蛋白质复合物的调节提供新的线索，该蛋白质复合物对髓鞘的发育和功能至关重要。了解控制髓鞘中蛋白质复合物的组装、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.