Abstract
Neurons are highly specialized cells of the nervous system that receive, process and transmit electrical signals critical for normal brain function. Here, we review the intricate organization of axonal membrane domains that facilitate rapid action potential conduction underlying communication between complex neuronal circuits. Two critical excitable domains of vertebrate axons are the axon initial segment (AIS) and the nodes of Ranvier, which are characterized by the high concentrations of voltage-gated ion channels, cell adhesion molecules and specialized cytoskeletal networks. The AIS is located at the proximal region of the axon and serves as the site of action potential initiation, while nodes of Ranvier, gaps between adjacent myelin sheaths, allow rapid propagation of the action potential through saltatory conduction. The AIS and nodes of Ranvier are assembled by ankyrins, spectrins and their associated binding partners through the clustering of membrane proteins and connection to the underlying cytoskeleton network. Although the AIS and nodes of Ranvier share similar protein composition, their mechanisms of assembly are strikingly different. Here we will cover the mechanisms of formation and maintenance of these axonal excitable membrane domains, specifically highlighting the similarities and differences between them. We will also discuss recent advances in super resolution fluorescence imaging which have elucidated the arrangement of the submembranous axonal cytoskeleton revealing a surprising structural organization necessary to maintain axonal organization and function. Finally, human mutations in axonal domain components have been associated with a growing number of neurological disorders including severe cognitive dysfunction, epilepsy, autism, neurodegenerative diseases and psychiatric disorders. Overall, this review highlights the assembly, maintenance and function of axonal excitable domains, particularly the AIS and nodes of Ranvier, and how abnormalities in these processes may contribute to disease.
Highlights
Neurons are polarized cells made up of structurally and functionally distinct processes, dendrites and axons, which direct the flow of information throughout the nervous system
The results showed an array of microtubule bundles covered in a dense submembranous coat comprised of known axon initial segment (AIS) proteins including ankyrin-G, βIV-spectrin, neurofascin, Nav channels and actin filaments (Jones et al, 2014)
The molecular composition between peripheral nervous system (PNS) and central nervous system (CNS) nodes of Ranvier are similar, the mechanisms involved in their assembly are different mainly due to the glial cells types involved in myelination (Figure 4)
Summary
Neurons are polarized cells made up of structurally and functionally distinct processes, dendrites and axons, which direct the flow of information throughout the nervous system. The axon propagates electrical signals, known as action potentials, to downstream neurons by the opening of voltage gated-sodium channels at specialized excitable microdomains referred to as the axon initial segment (AIS) and nodes of Ranvier (Figure 1). Action potential initiation at the AIS and efficient propagation across the nodes of Ranvier requires the localization of high concentrations of voltage-gated ion channels. The AIS and nodes contain high densities of cell adhesion molecules and scaffolding proteins that anchor these critical ion channels to the underlying cytoskeleton networks. The intricate formation and function of excitable axonal microdomains of the vertebrate nervous system plays a critical role in fast neuronal signaling and higher order cognitive processing. This review focuses on the recent advances in our understanding of structural and functional mechanisms underlying the formation and function of AIS and nodes of Ranvier and how disruptions in these mechanisms influence neurological health and disease
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