Ankyrin-Dependent and -Independent Mechanisms Orchestrate Axonal Compartmentalization of L1 Family Members Neurofascin and L1/Neuron–Glia Cell Adhesion Molecule

Boiko, Tatiana; Vakulenko, Max; Ewers, Helge; Yap, Chan Choo; Norden, Caren; Winckler, Bettina

doi:10.1523/jneurosci.4302-06.2007

Cited by 100 publications

(123 citation statements)

References 79 publications

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“…Released Kv3.1b channel proteins may cross the AIS barrier through intracellular transport mediated by motor proteins and/or passive diffusion. Finally, it is important to note that our studies do not exclude the involvement of other proteins in the targeting process, because precise targeting of neuronal membrane proteins likely requires multiple steps (Boiko et al, 2007). Our results suggest that ankyrin G plays a key role in controlling axon-dendrite targeting of Kv3.1 channels, and lay the foundation for additional studies aimed at a complete understanding of Kv3 channel targeting and function in neurons.…”

Section: Direct Interaction Between the T1 Domain And The Atm Regionmentioning

confidence: 88%

The Axon–Dendrite Targeting of Kv3 (Shaw) Channels Is Determined by a Targeting Motif That Associates with the T1 Domain and Ankyrin G

Xu¹,

Cao²,

Xiao³

et al. 2007

J. Neurosci.

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Kv3 (Shaw) channels regulate rapid spiking, transmitter release and dendritic integration of many central neurons. Crucial to functional diversity are the complex targeting patterns of channel proteins. However, the targeting mechanisms are not known. Here we report that the axon-dendrite targeting of Kv3.1 is controlled by a conditional interaction of a C-terminal axonal targeting motif (ATM) with the N-terminal T1 domain and adaptor protein ankyrin G. In cultured hippocampal neurons, although the two splice variants of Kv3.1, Kv3.1a and Kv3.1b, are differentially targeted to the somatodendritic and axonal membrane, respectively, the lysine-rich ATM is surprisingly common for both splice variants. The ATM not only directly binds to the T1 domain in a Zn 2ϩ -dependent manner, but also associates with the ankyrin-repeat domain of ankyrin G. However, the full-length channel proteins of Kv3.1b display stronger association to ankyrin G than those of Kv3.1a, suggesting that the unique splice domain at Kv3.1b C terminus influences ATM binding to T1 and ankyrin G. Because ankyrin G mainly resides at the axon initial segment, we propose that it may function as a barrier for axon-dendrite targeting of Kv3.1 channels. In support of this idea, disrupting ankyrin G function either by over-expressing a dominant-negative mutant or by siRNA knockdown decreases polarized axon-dendrite targeting of both Kv3.1a and Kv3.1b. We conclude that the conditional ATM masked by the T1 domain in Kv3.1a is exposed by the splice domain in Kv3.1b, and is subsequently recognized by ankyrin G to target Kv3.1b into the axon.

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Section: Direct Interaction Between the T1 Domain And The Atm Regionmentioning

confidence: 88%

The Axon–Dendrite Targeting of Kv3 (Shaw) Channels Is Determined by a Targeting Motif That Associates with the T1 Domain and Ankyrin G

Xu¹,

Cao²,

Xiao³

et al. 2007

J. Neurosci.

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“…It has been previously shown that L1 mainly interacts with ankyrinB (Boiko et al, 2007), which in turns stabilizes L1 within the axon. Moreover, other members of the L1CAM family of cell adhesion molecules, such as neurofascin and NrCAM, interact with ankyrinG (Bennett and Chen, 2001), which mediates clustering of Na + channels at the AIS Barry et al, 2014).…”

Section: Deletion Of L1 Reduces Neuronal Intrinsic Excitability Of Exmentioning

confidence: 99%

Cell adhesion molecule L1 contributes to neuronal excitability regulating the function of voltage-gated Na+ channels

Valente

Lignani

Medrihan

et al. 2016

Journal of Cell Science

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L1 (also known as L1CAM) is a trans-membrane glycoprotein mediating neuron-neuron adhesion through homophilic and heterophilic interactions. Although experimental evidence has implicated L1 in axonal outgrowth, fasciculation and pathfinding, its contribution to voltage-gated Na + channel function and membrane excitability has remained unknown. Here, we show that firing rate, single cell spiking frequency and Na + current density are all reduced in hippocampal excitatory neurons from L1-deficient mice both in culture and in slices owing to an overall reduced membrane expression of Na + channels. Remarkably, normal firing activity was restored when L1 was reintroduced into L1-deficient excitatory neurons, indicating that abnormal firing patterns are not related to developmental abnormalities, but are a direct consequence of L1 deletion. Moreover, L1 deficiency leads to impairment of action potential initiation, most likely due to the loss of the interaction of L1 with ankyrin G that produces the delocalization of Na + channels at the axonal initial segment. We conclude that L1 contributes to functional expression and localization of Na + channels to the neuronal plasma membrane, ensuring correct initiation of action potential and normal firing activity.

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“…3A and Fig. S4) (19). We next used surface plasmon resonance (SPR) experiments to assess the direct interaction between EB3 and ankG.…”

Section: Eb3mentioning

confidence: 99%

End-binding proteins EB3 and EB1 link microtubules to ankyrin G in the axon initial segment

Leterrier

Vacher

Fache

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

148

152

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The axon initial segment (AIS) plays a key role in maintaining the molecular and functional polarity of the neuron. The relationship between the AIS architecture and the microtubules (MTs) supporting axonal transport is unknown. Here we provide evidence that the MT plus-end-binding (EB) proteins EB1 and EB3 have a role in the AIS in addition to their MT plus-end tracking protein behavior in other neuronal compartments. In mature neurons, EB3 is concentrated and stabilized in the AIS. We identified a direct interaction between EB3/EB1 and the AIS scaffold protein ankyrin G (ankG). In addition, EB3 and EB1 participate in AIS maintenance, and AIS disassembly through ankG knockdown leads to cell-wide up-regulation of EB3 and EB1 comets. Thus, EB3 and EB1 coordinate a molecular and functional interplay between ankG and the AIS MTs that supports the central role of ankG in the maintenance of neuronal polarity. N eurons are highly polarized cells that rely on microtubules (MTs) for maintenance of their architecture and long-range polarized trafficking (1). MTs supporting axonal transport travel through the axon initial segment (AIS), a compartment that is essential for the generation of action potentials (2) and the maintenance of neuronal polarity (3). Generation of action potentials depends on the concentration of voltage-gated sodium (Nav) and potassium channels at the AIS, which are tethered at the plasma membrane via their interaction with ankyrin G (ankG (4-7). ankG, in turn, is linked to the actin cytoskeleton via βIV-spectrin and organizes AIS formation by recruiting membrane proteins and βIV-spectrin to the nascent AIS (3).The AIS maintains neuronal polarity by forming a diffusion barrier for membrane constituents at the cell surface (4,8,9) and also by dampening intracellular diffusion and vesicular transport through the AIS (10). Both phenomena depend on ankG, because depletion of ankG results in the disappearance of AIS and the acquisition of dendritic identity by the proximal axon (11,12). However, the molecular role of ankG in the intracellular AIS organization is still unknown. The dependence of the AIS intracellular filter on ankG (10) and the disorganization of MT bundles in the AIS of Purkinje cells from ankG-deficient mice (12) suggest an unknown link between ankG and MTs in the AIS.The end-binding (EB) proteins family, composed of three members (EB1-3), has been described as plus-end-tracking proteins (+TIPs) that coordinate a network of dynamic proteins on the growing MT plus-ends (13). In neurons, EB1 has been implicated in axonal transport (14, 15), whereas EB3 has been characterized as a molecular link between MTs and the actin cytoskeleton (16, 17). We hypothesized that EB proteins could have a role in the AIS via interaction with the ankG/βIV-spectrin scaffold. We first found that EB3 is accumulated and stabilized in the AIS of mature neurons. Both EB3 and EB1 bind to ankG and participate in the maintenance of the AIS scaffold. Reciprocally, altering neuronal polarity through ankG knockdown in...

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Ankyrin-Dependent and -Independent Mechanisms Orchestrate Axonal Compartmentalization of L1 Family Members Neurofascin and L1/Neuron–Glia Cell Adhesion Molecule

Cited by 100 publications

References 79 publications

The Axon–Dendrite Targeting of Kv3 (Shaw) Channels Is Determined by a Targeting Motif That Associates with the T1 Domain and Ankyrin G

The Axon–Dendrite Targeting of Kv3 (Shaw) Channels Is Determined by a Targeting Motif That Associates with the T1 Domain and Ankyrin G

Cell adhesion molecule L1 contributes to neuronal excitability regulating the function of voltage-gated Na+ channels

End-binding proteins EB3 and EB1 link microtubules to ankyrin G in the axon initial segment

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