The Microtubule Plus-End Tracking Protein EB1 Is Required for Kv1 Voltage-Gated K+ Channel Axonal Targeting

Gu, Chen; Zhou, Wei; Puthenveedu, Manojkumar A.; Xu, Mingxuan; Jan, Yuh Nung

doi:10.1016/j.neuron.2006.10.022

Cited by 125 publications

(142 citation statements)

References 55 publications

(91 reference statements)

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“…S7) (17). In contrast, EB1 localizes in somatic puncta and along axons (15), with accumulation in the AIS for a subpopulation of neurons, as previously observed (Fig. 5C) (14).…”

Section: Ankg Binds To the End-binding Homology Domain Hydrophobicsupporting

confidence: 84%

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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.

144

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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“…S7) (17). In contrast, EB1 localizes in somatic puncta and along axons (15), with accumulation in the AIS for a subpopulation of neurons, as previously observed (Fig. 5C) (14).…”

Section: Ankg Binds To the End-binding Homology Domain Hydrophobicsupporting

confidence: 84%

“…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.…”

mentioning

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.

144

152

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“…Previous studies identified some cargos of Kif5C, including GABA receptors (22), axonal synaptic vesicle precursors (23), APP-containing vesicles (24,25), TrkB vesicles (26), mitochondria (23,(27)(28)(29)(30)(31), AMPAR vesicles (32), and mRNA/protein complexes (33,34). Kif3 was shown to transport fodrin-associating vesicles in cultured superior cervical ganglion neurons (35), Ncadherin in the developing mouse brain (36) and axonal voltagegated potassium channel in cultured hippocampal neurons (37). Approximately 40-50% of the protein cargos identified in our proteomics analysis of three kinesin complexes are known synaptic proteins (highlighted in SI Appendix, Dataset S1).…”

Section: Discussionmentioning

confidence: 98%

New approach to capture and characterize synaptic proteome

Liu¹,

Kadakkuzha²,

Pascal³

et al. 2014

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

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Little is known regarding the identity of the population of proteins that are transported and localized to synapses. Here we describe a new approach that involves the isolation and systematic proteomic characterization of molecular motor kinesins to identify the populations of proteins transported to synapses. We used this approach to identify and compare proteins transported to synapses by kinesin (Kif) complexes Kif5C and Kif3A in the mouse hippocampus and prefrontal cortex. Approximately 40-50% of the protein cargos identified in our proteomics analysis of kinesin complexes are known synaptic proteins. We also found that the identity of kinesins and where they are expressed determine what proteins they transport. Our results reveal a previously unappreciated role of kinesins in regulating the composition of synaptic proteome.kinesin | protein transport | synapse | proteome | hippocampus

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“…Inhibition of microtubule growth or depletion of EB3, one of the major microtubule plusend binding proteins in mature neurons, caused the specific loss of mushroom-headed spines and increased the percentage of filopodia (Jaworski et al, 2009). Live imaging revealed that dynamic microtubules regularly depart from the dendritic shaft and enter dendritic spines (Gu et al, 2006;Hu et al, 2008;Jaworski et al, 2009) to stimulate actin polymerization and induce transient morphological changes, such as the formation of spine head protrusions or spine growth (Jaworski et al, 2009). These observations support a model in which EB3 plus-end decorated microtubules control actin dynamics and regulate spine morphology and synaptic plasticity.…”

Section: Introductionmentioning

confidence: 99%

NMDA Receptor Activation Suppresses Microtubule Growth and Spine Entry

Kapitein

Yau²,

Gouveia³

et al. 2011

J. Neurosci.

106

105

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Dynamic microtubules are important to maintain neuronal morphology and function, but whether neuronal activity affects the organization of dynamic microtubules is unknown. Here, we show that a protocol to induce NMDA-dependent long-term depression (LTD) rapidly attenuates microtubule dynamics in primary rat hippocampal neurons, removing the microtubule-binding protein EB3 from the growing microtubule plus-ends in dendrites. This effect requires the entry of calcium and is mediated by activation of NR2B-containing NMDA-type glutamate receptor. The rapid NMDA effect is followed by a second, more prolonged response, during which EB3 accumulates along MAP2-positive microtubule bundles in the dendritic shaft. MAP2 is both required and sufficient for this activity-dependent redistribution of EB3. Importantly, NMDA receptor activation suppresses microtubule entry in dendritic spines, whereas overexpression of EB3-GFP prevents NMDA-induced spine shrinkage. These results suggest that short-lasting and long-lasting changes in dendritic microtubule dynamics are important determinants for NMDA-induced LTD.

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The Microtubule Plus-End Tracking Protein EB1 Is Required for Kv1 Voltage-Gated K+ Channel Axonal Targeting

Cited by 125 publications

References 55 publications

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

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

New approach to capture and characterize synaptic proteome

NMDA Receptor Activation Suppresses Microtubule Growth and Spine Entry

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