Voltage-gated ion channels shape the physiological properties of neurons. Their vital role in normal nervous system function not only depends on their intrinsic biophysical properties but also on their surface density and cellular distribution. This PhD project is part of a larger research programme that aims to determine how ion channel surface density and cellular distribution is regulated and is founded on our discovery that the high-density accumulation of shaker type voltage-gated potassium channels (Kv1) at specific axonal domains critically depends on members of a small family of secreted proteins and their receptors (Leucine-rich Glioma-Inactivated, LGI and A Disintegrin And Metalloprotease, ADAM families respectively). Mutations or autoimmune disease affecting shaker type potassium channels, LGI and ADAM proteins are associated with epilepsy, ataxia and encephalitis, but the functional interactions between these proteins remain poorly understood.
Through the use of super resolution light microscopy and 3D electron microscopy we will explore the cellular distribution of Kv1 channels, Adam23/22 and its ligands Lgi2 and Lgi3 in myelinated axons of the developing peripheral and central nervous system of wildtype and Lgi3/2 and Adam23 mutant mice. In addition, we will study the interaction between Kv1 and Adam23/Lgi3 by a novel biotinylation technology, immune-precipitation, Western blotting and mass spectrometry to reveal the mechanism through which Lgi proteins direct the correct targeting and assembly of Kv1 protein complexes. Furthermore, we will establish how the specific localization of Kv1 channel clusters contributes to the electro-physiological properties of myelinated axons.