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

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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.