ReviewComposition, assembly, and maintenance of excitable membrane domains in myelinated axons
Introduction
To facilitate rapid action potential conduction, mammalian neurons have evolved a remarkable set of ion channel clustering mechanisms [1], some of which are just now being discovered. Clustered ion channels at the most proximal part of the axon, or the axon initial segment (AIS; Fig. 1A), function to integrate synaptic input into a single all-or-none response called the action potential (AP). Once generated, the AP must propagate rapidly and efficiently over very long distances; in mammalian myelinated axons, Na+ channels clustered at regularly spaced gaps in the myelin sheath called nodes of Ranvier (Fig. 1B, green) perform this function. Nodal channels are responsible for regenerating the inward Na+ currents that underlie saltatory AP conduction. In addition to Na+ channels, K+ channels are also highly clustered at discrete locations along axons where they modulate AP amplitude, duration, and frequency of firing [2]. These axonal membrane domains have been the focus of renewed attention as it has become clear their molecular compositions and physiologies are more diverse and plastic than originally thought, and because these domains represent a remarkable example of how neurons and their associated glial cells can regulate their membrane properties and protein localization to reflect their special functions. Here, I discuss the protein components that have been identified at the AIS and nodes of Ranvier, and describe how these domains are assembled during development. Finally, diseases and injuries can alter the functional organization of axons by disrupting AIS and nodes of Ranvier. I will discuss the evidence to support this previously unappreciated consequence of injury. Due to space limitations, I will not provide an exhaustive description of each molecule and domain or physiologies, but I will highlight key ideas that reflect principles of organization and function.
Section snippets
Ion channels
The excitable domains along axons share a common molecular organization consisting of ion channels, cell adhesion molecules, cytoskeletal and scaffolding proteins, and extracellular matrix molecules. In some cases, two different domains can have virtually identical compositions! Of course, the main characteristic of the membrane domains discussed here is that they are highly enriched with voltage-gated ion channels. Both AIS and nodes of Ranvier have high densities of voltage-gated Na+ (Nav)
Assembly of axonal domains
Although nodes, juxtaparanodes, and AIS share a common molecular organization, their mechanisms of assembly are distinct. The major difference is that AIS are intrinsically organized by the neuron, i.e. neurons contain all the necessary ‘ingredients’ to assemble an AIS. In contrast, despite having the necessary axonal ‘ingredients’, a node of Ranvier or a juxtaparanode will not form in the absence of glial-derived signals and neuron–glia interactions. Thus, AIS form from the inside-out, while
Maintenance of axonal domains
In addition to the membrane specializations found along axons, neurons are subdivided into two major polarized domains: the axonal and somatodendritic domains, each of which is populated by unique sets of molecules that are important for synaptic input and integration (somatodendritic domain) or action potential propagation (axonal domain). The junction between these two domains corresponds to the AIS, and proteins and lipids found here are remarkably stable with very long half-lives or
Axonal domains in disease
Since the clustering of Na+ and K+ channels at nodes and juxtaparanodes depends on neuron–glia interactions, it is not surprising that demyelination, dysmyelination, and altered neuron–glia interactions leads to loss of nodal and juxtaparanodal ion channel clusters and altered nerve conduction [76], [77], [78], [79]. Demyelination and disrupted neuron–glia interactions also results in the upregulation of Nav1.2 in several CNS disease models [78], [80], [81], while demyelination in Trembler-J
Conclusion
Clustering of ion channels along axons is essential to normal nervous system function. While some of the proteins that contribute to clustering have been identified, our knowledge of the composition of these domains remains rudimentary. This limitation has impaired our ability to determine the mechanisms underlying assembly of these important axonal domains. Key questions that remain unanswered include: how is ankG restricted to the AIS? Do ECM proteins contribute to Nav channel clustering in
Acknowledgements
Supported by NIH grants NS044916 and NS069688. M.N.R. is a Harry Weaver Neuroscience Scholar of the National Multiple Sclerosis Society.
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Diseases of the Nervous System
2021, Diseases of the Nervous SystemOligodendrogliopathy in neurodegenerative diseases with abnormal protein aggregates: The forgotten partner
2018, Progress in NeurobiologyCitation Excerpt :MBP and PLP represent 80% of the total myelin protein. Nodes of Ranvier are enriched in certain myelin- and axon-derived proteins—netrin, contactin 1 and 2, neurofascin 155, neurofascin 186, contactin-associated proteins (Caspr 1 and 2)—which interact to bind the myelin sheath to the axon at the free borders of myelin, together with extracellular matrix proteins such as brevican, versican and N-CAM variant (Rasband, 2011; Thaxton et al., 2011; Susuki et al., 2013; Arancibia-Carcamo and Attwell, 2014; Griggs et al., 2017). Because of the large area of oligodendrocytes and cellular processes including myelin, these cells would be very vulnerable to energy metabolism deficiencies.
The axon-glia unit in white matter stroke: Mechanisms of damage and recovery
2015, Brain ResearchCitation Excerpt :Such changes in the axon–glia structure disrupt the spatial segregation of Na+ and K+ channels in the node and juxtaparanode areas. This segregation is critical to proper axonal conduction of action potentials and its perturbation has been suggested to contribute to many pathological conditions that involve failure of axonal function (Arroyo et al., 2002; Hinman et al., 2006; Rasband, 2011; Salzer et al., 2008). Studies in models of multiple sclerosis demonstrate that disrupted or less efficient axonal conductance may manifest as severely as a complete loss of axonal function, due in most to the spatial and temporal summation requirements that are the hallmark of neuronal signaling; for a target neuron to reach threshold, several action potentials (from one or more axons) must arrive to its synaptic terminals within a narrow time window.
CK2 accumulation at the axon initial segment depends on sodium channel Nav1
2014, FEBS LettersCitation Excerpt :In mammalian neurons, the generation and propagation of action potentials result from the presence of dense clusters of voltage-gated sodium channels (Nav1) at the axonal initial segment (AIS) and nodes of Ranvier [1,2]. In these two structures, the assembly of specific supra-molecular complexes, composed of numerous partners, such as cytoskeletal scaffold proteins and protein kinases, ensures the high concentration of Nav1 channels [3,4]. One key feature regulating Nav1 channel clustering is their binding to the scaffolding protein ankyrin G (ankG) via a highly conserved amino acid motif (ankyrin-binding motif) in their intracellular loop II–III [5,6].