scholarly journals Nodes of Ranvier and axon initial segments are ankyrin G–dependent domains that assemble by distinct mechanisms

2007 ◽  
Vol 177 (5) ◽  
pp. 857-870 ◽  
Author(s):  
Yulia Dzhashiashvili ◽  
Yanqing Zhang ◽  
Jolanta Galinska ◽  
Isabel Lam ◽  
Martin Grumet ◽  
...  
Keyword(s):  
Schwann Cells ◽  
Sodium Channels ◽  
Cytoskeletal Proteins ◽  
Action Potential Generation ◽  
Potential Generation ◽  
Nodes Of Ranvier ◽  
Ankyrin G ◽  
Sites Of Action ◽  
Axon Initial Segments ◽  
Inside Out

Axon initial segments (AISs) and nodes of Ranvier are sites of action potential generation and propagation, respectively. Both domains are enriched in sodium channels complexed with adhesion molecules (neurofascin [NF] 186 and NrCAM) and cytoskeletal proteins (ankyrin G and βIV spectrin). We show that the AIS and peripheral nervous system (PNS) nodes both require ankyrin G but assemble by distinct mechanisms. The AIS is intrinsically specified; it forms independent of NF186, which is targeted to this site via intracellular interactions that require ankyrin G. In contrast, NF186 is targeted to the node, and independently cleared from the internode, by interactions of its ectodomain with myelinating Schwann cells. NF186 is critical for and initiates PNS node assembly by recruiting ankyrin G, which is required for the localization of sodium channels and the entire nodal complex. Thus, initial segments assemble from the inside out driven by the intrinsic accumulation of ankyrin G, whereas PNS nodes assemble from the outside in, specified by Schwann cells, which direct the NF186-dependent recruitment of ankyrin G.

scholarly journals Neurodevelopmental mutation of giant ankyrin-G disrupts a core mechanism for axon initial segment assembly

2019 ◽  
Vol 116 (39) ◽  
pp. 19717-19726 ◽  
Author(s):  
Rui Yang ◽  
Kathryn K. Walder-Christensen ◽  
Samir Lalani ◽  
Haidun Yan ◽  
Irene Díez García-Prieto ◽  
...  
Keyword(s):  
Neural Development ◽  
Initial Segment ◽  
Intermediate Stage ◽  
Missense Mutations ◽  
Action Potential Generation ◽  
Potential Generation ◽  
Close Apposition ◽  
Ankyrin G ◽  
Sites Of Action ◽  
Axon Initial Segments

Giant ankyrin-G (gAnkG) coordinates assembly of axon initial segments (AISs), which are sites of action potential generation located in proximal axons of most vertebrate neurons. Here, we identify a mechanism required for normal neural development in humans that ensures ordered recruitment of gAnkG and β4-spectrin to the AIS. We identified 3 human neurodevelopmental missense mutations located in the neurospecific domain of gAnkG that prevent recruitment of β4-spectrin, resulting in a lower density and more elongated pattern for gAnkG and its partners than in the mature AIS. We found that these mutations inhibit transition of gAnkG from a closed configuration with close apposition of N- and C-terminal domains to an extended state that is required for binding and recruitment of β4-spectrin, and normally occurs early in development of the AIS. We further found that the neurospecific domain is highly phosphorylated in mouse brain, and that phosphorylation at 2 sites (S1982 and S2619) is required for the conformational change and for recruitment of β4-spectrin. Together, these findings resolve a discrete intermediate stage in formation of the AIS that is regulated through phosphorylation of the neurospecific domain of gAnkG.

scholarly journals βIVΣ1 spectrin stabilizes the nodes of Ranvier and axon initial segments

2004 ◽  
Vol 166 (7) ◽  
pp. 983-990 ◽  
Author(s):  
Sandra Lacas-Gervais ◽  
Jun Guo ◽  
Nicola Strenzke ◽  
Eric Scarfone ◽  
Melanie Kolpe ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Actin Binding ◽  
Ultrastructural Changes ◽  
Nodes Of Ranvier ◽  
Ankyrin G ◽  
Voltage Gated Sodium Channels ◽  
Dense Membrane ◽  
Afferent Fibers ◽  
Actin Binding Domain ◽  
Axon Initial Segments

Saltatory electric conduction requires clustered voltage-gated sodium channels (VGSCs) at axon initial segments (AIS) and nodes of Ranvier (NR). A dense membrane undercoat is present at these sites, which is thought to be key for the focal accumulation of channels. Here, we prove that βIVΣ1 spectrin, the only βIV spectrin with an actin-binding domain, is an essential component of this coat. Specifically, βIVΣ1 coexists with βIVΣ6 at both AIS and NR, being the predominant spectrin at AIS. Removal of βIVΣ1 alone causes the disappearance of the nodal coat, an increased diameter of the NR, and the presence of dilations filled with organelles. Moreover, in myelinated cochlear afferent fibers, VGSC and ankyrin G clusters appear fragmented. These ultrastructural changes can explain the motor and auditory neuropathies present in βIVΣ1 −/− mice and point to the βIVΣ1 spectrin isoform as a master-stabilizing factor of AIS/NR membranes.

scholarly journals βIV-spectrin regulates sodium channel clustering through ankyrin-G at axon initial segments and nodes of Ranvier

2002 ◽  
Vol 156 (2) ◽  
pp. 337-348 ◽  
Author(s):  
Masayuki Komada ◽  
Philippe Soriano
Keyword(s):  
Sodium Channels ◽  
Embryonic Stem ◽  
Nodes Of Ranvier ◽  
Gene Trapping ◽  
Voltage Gated ◽  
Ankyrin G ◽  
Membrane Cytoskeleton ◽  
Voltage Gated Sodium Channels ◽  
Axon Initial Segments ◽  
Sodium Channel Clustering

β-Spectrin and ankyrin are major components of the membrane cytoskeleton. We have generated mice carrying a null mutation in the βIV-spectrin gene using gene trapping in embryonic stem cells. Mice homozygous for the mutation exhibit tremors and contraction of hindlimbs. βIV-spectrin expression is mostly restricted to neurons, where it colocalizes with and binds to ankyrin-G at axon initial segments (AISs) and nodes of Ranvier (NR). In βIV-spectrin–null neurons, neither ankyrin-G nor voltage-gated sodium channels (VGSC) are correctly clustered at these sites, suggesting that impaired action potential caused by mislocalization of VGSC leads to the phenotype. Conversely, in ankyrin-G–null neurons, βIV-spectrin is not localized to these sites. These results indicate that βIV-spectrin and ankyrin-G mutually stabilize the membrane protein cluster and the linked membrane cytoskeleton at AIS and NR.

Sites of action potential generation in cultured vertebrate neurons

1983 ◽  
Vol 288 (1-2) ◽  
pp. 381-383 ◽  
Author(s):  
T.G. Smith
Keyword(s):  
Action Potential ◽  
Action Potential Generation ◽  
Potential Generation ◽  
Sites Of Action

Sites of action potential generation in Helix pomatia neurons

1988 ◽  
Vol 20 (1) ◽  
pp. 73-79
Author(s):  
V. N. Ierusalimskii ◽  
P. M. Balaban
Keyword(s):  
Action Potential ◽  
Helix Pomatia ◽  
Action Potential Generation ◽  
Potential Generation ◽  
Sites Of Action

scholarly journals Proteolysis of Submembrane Cytoskeletal Proteins Ankyrin-G and αII-Spectrin Following Diffuse Brain Injury: A Role in White Matter Vulnerability at Nodes of Ranvier

2010 ◽  
Vol 20 (6) ◽  
pp. 1055-1068 ◽  
Author(s):  
Thomas M. Reeves ◽  
John E. Greer ◽  
Andrew S. Vanderveer ◽  
Linda L. Phillips
Keyword(s):  
Brain Injury ◽  
White Matter ◽  
Cytoskeletal Proteins ◽  
Nodes Of Ranvier ◽  
Diffuse Brain Injury ◽  
Ankyrin G ◽  
Diffuse Brain

scholarly journals Voltage-gated sodium channels in neocortical pyramidal neurons display Cole-Moore activation kinetics

2017 ◽  
Author(s):  
Mara Almog ◽  
Tal Barkai ◽  
Angelika Lampert ◽  
Alon Korngreen
Keyword(s):  
Action Potential ◽  
Sodium Channels ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Action Potential Generation ◽  
Potential Generation ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Gating Mechanism ◽  
Cortical Pyramidal Neurons

AbstractExploring the properties of action potentials is a crucial step towards a better understanding of the computational properties of single neurons and neural networks. The voltage-gated sodium channel is a key player in action potential generation. A comprehensive grasp of the gating mechanism of this channel can shed light on the biophysics of action potential generation. Most models of voltage-gated sodium channels assume it obeys a concerted Hodgkin and Huxley kinetic gating scheme. Here we performed high resolution voltage-clamp experiments from nucleated patches extracted from the soma of layer 5 (L5) cortical pyramidal neurons in rat brain slices. We show that the gating mechanism does not follow traditional Hodgkin and Huxley kinetics and that much of the channel voltage-dependence is probably due to rapid closed-closed transitions that lead to substantial onset latency reminiscent of the Cole-Moore effect observed in voltage-gated potassium conductances. This may have key implications for the role of sodium channels in synaptic integration and action potential generation.

scholarly journals Differential Contribution of Sodium Channel Subtypes to Action Potential Generation in Unmyelinated Human C-type Nerve Fibers

2007 ◽  
Vol 107 (3) ◽  
pp. 495-501 ◽  
Author(s):  
Philip M. Lang ◽  
Verena B. Hilmer ◽  
Peter Grafe
Keyword(s):  
Action Potential ◽  
Sodium Channels ◽  
Action Potentials ◽  
Peak Height ◽  
Nerve Fibers ◽  
Action Potential Generation ◽  
Potential Generation ◽  
Compound C ◽  
C Fiber ◽  
Voltage Dependent

Background Multiple voltage-dependent sodium channels (Na(v)) contribute to action potentials and excitability of primary nociceptive neurons. The aim of the current study was to characterize subtypes of Na(v) that contribute to action potential generation in peripheral unmyelinated human C-type nerve fibers. Methods Registration of C-fiber compound action potentials and determination of membrane threshold was performed by a computerized threshold tracking program. Nerve fibers were stimulated with a 1-ms current pulse either alone or after a small ramp current lasting 300 ms. Results Compound C-fiber action potentials elicited by supramaximal 1-ms current pulses were rather resistant to application of tetrodotoxin (30-90 nM). However, the same concentrations of tetrodotoxin strongly reduced the peak height and elevated membrane threshold of action potentials evoked at the end of a 300-ms current ramp. A similar effect was observed during application of lidocaine and mexiletine (50 microM each). Conclusions These data indicate that more than one type of Na(v) contributes to the generation of action potentials in unmyelinated human C-type nerve fibers. The peak height of an action potential produced by a short electrical impulse is dependent on the activation of tetrodotoxin-resistant ion channels. In contrast, membrane threshold and action potential peak height at the end of a slow membrane depolarization are regulated by a subtype of Na(v) with high sensitivity to low concentrations of tetrodotoxin, lidocaine, and mexiletine. The electrophysiologic and pharmacologic characteristics may indicate the functional activity of the Na(v) 1.7 subtype of voltage-dependent sodium channels.

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