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J Cell Sci. 2017 Jul 1;130(13):2209-2220. doi: 10.1242/jcs.202267. Epub 2017 May 22.

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

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Aix-Marseille Université, CNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Marseille UMR7286, France.
Institut Neuromyogène, CNRS UMR 5310, INSERM U1217, Université Claude Bernard Lyon 1, 69 372 Lyon, France.
Department of Basic Sciences, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, University of Crete, Heraklion, Crete 711 10, Greece.
Aix-Marseille Université, CNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Marseille UMR7286, France


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.


Axon initial segment; Axonal transport; Cell adhesion molecule; Juxtaparanode; Polarity

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