Molecular mechanisms of voltage-gated potassium channel clustering in myelinated axons

我们的感觉器官，如我们的眼睛或皮肤，与我们的大脑和脊髓之间的交流是通过神经传递的电信号进行的。神经是由称为轴突的神经延伸束组成的。轴突通过特定通道，通过钠离子和钾离子在轴突膜上的调节通量传导这些信号。我们神经中的许多轴突都被一层叫做髓磷脂的脂肪层所隔离，髓磷脂是由雪旺细胞和少突胶质细胞等支持细胞制造和维持的。髓磷脂层极大地加速了神经信号的传递，使我们能够对任何身体上的挑战做出快速而准确的反应。髓磷脂加速信号传导的方式是通过在沿轴突有规则间隔的区域聚集高密度的不同离子通道。当髓磷脂层的完整性被破坏时，如在多发性硬化症或糖尿病中，这种排列和离子通道密度的重要性变得明显，这会改变甚至阻断传导。但这些离子通道是如何排列并保持在特定区域的，在很大程度上是未知的。在这项工作中，我们将研究驱动一种离子通道聚集的分子；钾通道的Kv1类。Kv1通道在正常的神经系统功能中发挥重要作用，编码这些蛋白质的基因突变引起共济失调和癫痫等神经系统疾病。这些通道在有髓鞘的轴突中密度非常高，但也存在于神经元的其他部分。我们发现这些通道在有髓鞘轴突中的特定位置是两种蛋白质的功能；ADAM23受体及其可溶性结合伙伴LGI3。我们将研究这些分子如何组装Kv1通道并使它们保持在固定位置。我们将确定参与这一过程的其他蛋白质，并确定当Kv1通道错误定位或从轴突膜上移除时，髓鞘轴突的传导特性是如何改变的。这些重要的见解将进一步加深我们对Kv1通道如何分布在有髓鞘轴突的理解，并告知我们调节神经元其他部分的Kv1通道以影响神经元及其参与的神经元网络的基本生理特性的机制，并导致治疗人类共济失调和癫痫疾病的潜在改进。

The communication between our sense organs, such as our eyes or skin, and our brain and spinal cord occurs through electrical signals that are carried by our nerves. Nerve are composed of bundles of neuronal extensions called axons. Axons conduct these signals through the regulated flux of Sodium and Potassium ions over the axonal membrane through specific channels. Many of the axons in our nerves are insulated by a fatty layer called myelin which is made and maintained by support cells called Schwann cells and oligodendrocytes. The myelin layer speeds up nerve signaling enormously, allowing us to respond rapidly and with great accuracy to any physical challenge coming our way. The way myelin speeds up signal conduction is by clustering different ion channels to high density at regularly spaced regions along the axon.The importance of this arrangement and density of ion channels becomes apparent when the integrity of the myelin layer is damaged as in multiple sclerosis or in diabetes, which alters or even block conductance. But how these ion channels are arranged and kept in specific regions is largely unknown. In this work we will examine the molecules that drive the clustering of one type of ion channel; the Kv1 class of potassium channels. Kv1 channels play important roles in normal nervous system function and mutations in the genes that encode these proteins give rise to neurological diseases such Ataxia and epilepsy. These channels are found in very high density in myelinated axons but also in other parts of the neuron. We have discovered that the specific positioning of these channels in myelinated axons is a function of two proteins; the ADAM23 receptor and its soluble binding partner LGI3. We will investigate how these molecules assemble the Kv1 channels and keep them in their fixed position. We will identify what other proteins are involved in this process and we will determine how conduction properties of myelinated axons is altered when Kv1 channels are mis-localised or removed from the axonal membrane. These important insights will further our understanding of how Kv1 channels are distributed in myelinated axons and inform us about the mechanisms that regulate Kv1 channels in other parts of the neuron to affect the basic physiological properties of the neuron and the neuronal networks they participate in, and lead to potential improvements in treating human ataxic and epileptic disorders.