The Axon Initial Segment, 50Years Later

Leterrier, Christophe

doi:10.1016/bs.ctm.2015.10.005

Cited by 75 publications

(58 citation statements)

References 353 publications

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“…The diameter of the axon at the measurement locations was approximately 1 μm . We note that in pyramidal neurons, microtubules, and neurofilaments are located at a distance greater than 200 nm from the axonal membrane [24, 25]. Because the indentation depth in our experiments was approximately 100 nm , we do not expect that microtubules and neurofilaments will contribute to the measured axon plasma membrane stiffness.…”

Section: Materials and Modelsmentioning

confidence: 95%

“…Pyramidal neurons, which we used to experimentally determine the axonal membrane stiffness, have microtubules that are not structured in bundles but rather like a string of beads (in cross-section) [24, 25, 42] and they are at a distance greater than 200 nm from the axonal membrane [25]. Similarly, neurofilaments in pyramidal neurons are not arranged in bundles and are much farther away from the axonal membrane than microtubules [24].…”

Section: Materials and Modelsmentioning

confidence: 99%

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Modeling of the axon membrane skeleton structure and implications for its mechanical properties

Zhang

Abiraman

et al. 2017

PLoS Comput Biol

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Super-resolution microscopy recently revealed that, unlike the soma and dendrites, the axon membrane skeleton is structured as a series of actin rings connected by spectrin filaments that are held under tension. Currently, the structure-function relationship of the axonal structure is unclear. Here, we used atomic force microscopy (AFM) to show that the stiffness of the axon plasma membrane is significantly higher than the stiffnesses of dendrites and somata. To examine whether the structure of the axon plasma membrane determines its overall stiffness, we introduced a coarse-grain molecular dynamics model of the axon membrane skeleton that reproduces the structure identified by super-resolution microscopy. Our proposed computational model accurately simulates the median value of the Young’s modulus of the axon plasma membrane determined by atomic force microscopy. It also predicts that because the spectrin filaments are under entropic tension, the thermal random motion of the voltage-gated sodium channels (Nav), which are bound to ankyrin particles, a critical axonal protein, is reduced compared to the thermal motion when spectrin filaments are held at equilibrium. Lastly, our model predicts that because spectrin filaments are under tension, any axonal injuries that lacerate spectrin filaments will likely lead to a permanent disruption of the membrane skeleton due to the inability of spectrin filaments to spontaneously form their initial under-tension configuration.

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Section: Materials and Modelsmentioning

confidence: 95%

Section: Materials and Modelsmentioning

confidence: 99%

Modeling of the axon membrane skeleton structure and implications for its mechanical properties

Zhang

Abiraman

et al. 2017

PLoS Comput Biol

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“…A major player in the maintenance of this polarity is the axon initial segment (AIS), a specialized domain located within the first 50 µm of the axon. The AIS isolates the axon from the cell body and regulates protein exchange between the axonal and somatodendritic compartments (Rasband, 2010;Leterrier, 2016). Besides this important role in neuronal polarity, the AIS is also the site of generation of action potentials (Clark et al, 2009;Kole and Stuart, 2012).…”

Section: Introductionmentioning

confidence: 99%

Ankyrin G membrane partners drive the establishment and maintenance of the axon initial segment

Leterrier

Clerc

Rueda-Boroni

et al. 2016

Preprint

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The axon initial segment (AIS) is a highly specialized neuronal compartment that plays a key role in neuronal development and excitability. It concentrates multiple membrane proteins such as ion channels and cell adhesion molecules (CAMs) that are recruited to the AIS by the scaffold protein ankyrin G (ankG). The crucial function of ankG in the anchoring of AIS membrane components is well established, but a reciprocal role of membrane partners in ankG targeting and stabilization remained elusive. In rat cultured hippocampal neurons and cortical organotypic slices, we found that shRNA-mediated knockdown of ankG membrane partners (voltage-gated sodium channels (Nav) or neurofascin-186) led to a decrease of ankG concentration and perturbed the AIS formation and maintenance. These effects were rescued by expressing a recombinant AIS-targeted Nav or by a minimal construct containing the ankyrin-binding domain of Nav1.2 and a membrane anchor (mABD). Moreover, overexpressing mABD in mature neurons led to ankG mislocalization. Altogether, these results demonstrate that a tight and precocious association of ankG with its membrane partners is a key step for the establishment and maintenance of the AIS.

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“…Kv2.2 is expressed in large clusters in brain neurons, including on the axon initial segment or AIS (18, 66), a subcellular compartment highly enriched for components of the actin cortical cytoskeleton including a specialized complex of spectrins and ankyrins (67). We immunolabeled brain sections for Kv2.2 and ankyrinG (ankG), which is highly expressed at the AIS.…”

Section: Resultsmentioning

confidence: 99%

Organizing neuronal ER-PM junctions is a conserved nonconducting function of Kv2 plasma membrane ion channels

Kirmiz

Palacio

Thapa

et al. 2018

Preprint

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27Endoplasmic reticulum (ER) and plasma membrane (PM) form junctions crucial to ion and lipid 28 signaling and homeostasis. The Kv2.1 ion channel is unique among PM proteins in organizing 29 ER-PM junctions. Here, we show that this organizing function is conserved between Kv2 family 30 members that differ in their biophysical properties, modulation and cellular expression. 31Manipulation of actin cytoskeleton surrounding Kv2 ER-PM junctions affects their spatial 32 organization. Kv2-containing ER-PM junctions overlap with those formed by canonical ER-PM 33 tethers. ER-PM junction organization by Kv2 channels is unchanged by point mutations that 34 eliminate ion conduction, but abolished by those that eliminate PM clustering without impacting 35 ion channel function. Kv2.2 is distinct in lacking the reversible modulation of junction organization 36 present in Kv2.1. Brain neurons in Kv2 double knockout mice have altered ER-PM junctions, 37 demonstrating a conserved in vivo function for Kv2 family members distinct from their canonical 38 role as ion-conducting channels shaping neuronal excitability. 39 40. CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/296731 doi: bioRxiv preprint first posted online Apr. 6, 2018; 3 Introduction 41Membrane contacts between the endoplasmic reticulum (ER) and plasma membrane (PM), or 42 ER-PM junctions, are a ubiquitous feature of eukaryotic cells (1-4). These specialized sites at 43 which ER is held in close apposition (10-30 nm) and other excitable and non-excitable cell types. In brain neurons, Kv2 channels are distinct from 63 other Kv channels (17) in being specifically localized to high-density micron sized clusters 64 prominent on the soma, proximal dendrites, and axon initial segment (34-42). Kv2 channels also 65 form such clusters when exogenously expressed in cultured neurons and in heterologous cells 66 . CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/296731 doi: bioRxiv preprint first posted online Apr. 6, 2018; 4 (35, 37, 39, 41-47 at/near RyR clusters in specific neuron types, including hippocampal CA1 pyramidal neurons and 114 layer 6 neocortical neurons (Figure 1). A similar juxtaposition of Kv2.2 and RyR clusters was seen 115 in CHNs (Figure 1). In these classes of neurons, Kv2.2 was often found coclustered with Kv2.1 at 116 these ER-PM junctions (Figure 1). Neurons in each preparation also contained RyR clusters that 117 did not appear to colocalize with Kv2.2 or Kv2.1 (Figure 1). These findings demonstrate that Kv2.2 118 . CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted ...

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The Axon Initial Segment, 50Years Later

Cited by 75 publications

References 353 publications

Modeling of the axon membrane skeleton structure and implications for its mechanical properties

Modeling of the axon membrane skeleton structure and implications for its mechanical properties

Ankyrin G membrane partners drive the establishment and maintenance of the axon initial segment

Organizing neuronal ER-PM junctions is a conserved nonconducting function of Kv2 plasma membrane ion channels

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