Postsynaptic Density-93 Clusters Kv1 Channels at Axon Initial Segments Independently of Caspr2

Ogawa, Yasuhiro; Horresh, Ido; Trimmer, James S.; Bredt, David S.; Peles, Elior; Rasband, Matthew N.

doi:10.1523/jneurosci.4431-07.2008

Cited by 122 publications

(144 citation statements)

References 64 publications

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“…Caspr2 immunoreactivity was detected in the soma and axon, but not in dendrites, and was observed at the axonal initial segment as shown using double staining for Ankyrin-G (supplementary material Fig. S1) and as previously reported (Ogawa et al, 2008).…”

Section: Caspr2 Is Selectively Expressed At the Axonal Membrane Of Hisupporting

confidence: 85%

Axonal targeting of Caspr2 in hippocampal neurons via selective somatodendritic endocytosis

Bel

Oguievetskaia

Pitaval

et al. 2009

Journal of Cell Science

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Contactin-associated protein 2 (Caspr2) is a neuronal membrane protein that is mutated in autism and related disorders. Although it is highly enriched at juxtaparanodes of Ranvier where it is essential for Shaker-type K+ channel clustering, little is known about its function and regulation. In the present study, we examined the polarized expression of Caspr2 in hippocampal neurons using extracellular hemagglutinin (HA)-tagged Caspr2 constructs. We found that Caspr2 was targeted to the axonal surface, but colocalized with early endosomes in the somatodendritic compartment. The inhibition of endocytosis using a Dynamin-1 mutant or treatment with Dynasore prevented Caspr2 internalization from the dendrites and cell body. We identified a short sequence included into the 4.1B-binding domain that is required for the endocytosis of Caspr2. This sequence contains a protein kinase C (PKC) substrate motif on Thr1292, and point mutation of this residue or treatment with a PKC inhibitor prevented the somatodendritic internalization of Caspr2. Thus, the PKC-dependent trafficking of Caspr2 underlies its polarized expression in hippocampal neurons.

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Section: Caspr2 Is Selectively Expressed At the Axonal Membrane Of Hisupporting

confidence: 85%

Axonal targeting of Caspr2 in hippocampal neurons via selective somatodendritic endocytosis

Bel

Oguievetskaia

Pitaval

et al. 2009

Journal of Cell Science

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“…The PDZ-binding domain of Caspr2 is a type II binding sequence and does not interacting with type I PSD-93 or PSD-95 as reported for Kv1 channels (Ogawa et al, 2008). It was reported to associate with MAGuK proteins of the CASK and MPP2 family in GST pulldown assays .…”

Section: Caspr2 and Tag-1 Are Colocalized In Axonal Transport Vesiclesmentioning

confidence: 80%

“…In contrast to juxtaparanodes, Caspr2, and TAG-1, although present at the AIS are dispensable for the recruitment of Kv1 channels there (Duflocq et al, 2011;Inda et al, 2006;Ogawa et al, 2008). In addition, protein 4.1B is not enriched at the AIS while the membraneassociated guanylate kinase (MAGuK) PSD-93 (also known as DLG2) is present at that site (Duflocq et al, 2011;Ogawa et al, 2008). Other membrane proteins interacting with Kv1 channels could be localized at the AIS.…”

Section: Introductionmentioning

confidence: 97%

“…The intracellular protein 4.1B (also known as EPB41L3), which binds Caspr2 is required for assembling the juxtaparanodal scaffold (Buttermore et al, 2011;Cifuentes-Diaz et al, 2011;Einheber et al, 2013;Horresh et al, 2010). In contrast to juxtaparanodes, Caspr2, and TAG-1, although present at the AIS are dispensable for the recruitment of Kv1 channels there (Duflocq et al, 2011;Inda et al, 2006;Ogawa et al, 2008). In addition, protein 4.1B is not enriched at the AIS while the membraneassociated guanylate kinase (MAGuK) PSD-93 (also known as DLG2) is present at that site (Duflocq et al, 2011;Ogawa et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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The Kv1-associated molecules TAG-1 and Caspr2 are selectively targeted to the axon initial segment in hippocampal neurons

Pinatel

Hivert

Saint‐Martin

et al. 2017

Journal of Cell Science

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Caspr2 and TAG-1 (also known as CNTNAP2 and CNTN2, respectively) are cell adhesion molecules (CAMs) associated with the voltage-gated potassium channels Kv1.1 and Kv1.2 (also known as KCNA1 and KCNA2, respectively) at regions controlling axonal excitability, namely, the axon initial segment (AIS) and juxtaparanodes of myelinated axons. The distribution of Kv1 at juxtaparanodes requires axo-glial contacts mediated by Caspr2 and TAG-1. In the present study, we found that TAG-1 strongly colocalizes with Kv1.2 at the AIS of cultured hippocampal neurons, whereas Caspr2 is uniformly expressed along the axolemma. Live-cell imaging revealed that Caspr2 and TAG-1 are sorted together in axonal transport vesicles. Therefore, their differential distribution may result from diffusion and trapping mechanisms induced by selective partnerships. By using deletion constructs, we identified two molecular determinants of Caspr2 that regulate its axonal positioning. First, the LNG2-EGF1 modules in the ectodomain of Caspr2, which are involved in its axonal distribution. Deletion of these modules promotes AIS localization and association with TAG-1. Second, the cytoplasmic PDZ-binding site of Caspr2, which could elicit AIS enrichment and recruitment of the membrane-associated guanylate kinase (MAGuK) protein MPP2. Hence, the selective distribution of Caspr2 and TAG-1 may be regulated, allowing them to modulate the strategic function of the Kv1 complex along axons.

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“…In addition Kv1 channels are associated to the adhesion molecule Casppr2 in the layer 2/3 of the human cerebral cortex [76]. Silencing of PSD-93 expression in cultured hippocampal neurons blocks the recruitment of Kv1 channels to the AIS but not Na + channels [87]. The AIS is also enriched in the cell adhesion molecules Nr-CAM and Neurofascin-186, and the cytoskeletal linker ßIV spectrin [76].…”

Section: Associated Anchoring Proteins and Cytoskeletal Componentsmentioning

confidence: 99%

Projections, Partaken Circuits and Axon Initial Segments of Cortical Principal Neurons

Bueno‐López¹,

Chara²,

Mendizabal-Zubiaga³

et al. 2012

Visual Cortex - Current Status and Perspectives

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Postsynaptic Density-93 Clusters Kv1 Channels at Axon Initial Segments Independently of Caspr2

Cited by 122 publications

References 64 publications

Axonal targeting of Caspr2 in hippocampal neurons via selective somatodendritic endocytosis

Axonal targeting of Caspr2 in hippocampal neurons via selective somatodendritic endocytosis

The Kv1-associated molecules TAG-1 and Caspr2 are selectively targeted to the axon initial segment in hippocampal neurons

Projections, Partaken Circuits and Axon Initial Segments of Cortical Principal Neurons

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