Voltage-gated sodium channel organization in neurons: Protein interactions and trafficking pathways

In neurons, voltage-gated sodium (Nay) channels underlie the generation and propagation of the action potential. The proper targeting and concentration of Nay channels at the axon initial segment (AIS) and at the nodes of Ranvier are therefore vital for neuronal function. In AIS and nodes, Nay channels are part of specific supra-molecular complexes that include accessory proteins, adhesion proteins and cytoskeletal adaptors. Multiple approaches, from biochemical characterization of protein-protein interactions to functional studies using mutant mice, have addressed the mechanisms of Nay channel targeting to AIS and nodes. This review summarizes our current knowledge of both the intrinsic determinants and the role of partner proteins in Nay targeting. A few fundamental trafficking mechanisms, such as selective endocytosis and diffusion/retention, have been characterized. However, a lot of exciting questions are still open, such as the mechanism of differentiated Nay subtype localization and targeting, and the possible interplay between electrogenesis properties and Nay concentration at the AIS and the nodes. (C) 2010 Elsevier Ireland Ltd. All rights reserved.