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ADAM22 and ADAM23 modulate the targeting of the Kv1 channel-associated protein LGI1 to the axon initial segment.

Journal of Cell Science 2018 December 32
The distribution of voltage-gated potassium channels Kv1 at the axon initial segment (AIS) influences neuronal intrinsic excitability. Kv1.1/1.2 subunits are associated with cell adhesion molecules (CAMs), including Caspr2 and LGI1 that are implicated in autoimmune and genetic neurological diseases with seizures. In particular, mutations in the LGI1 gene cause autosomal dominant lateral temporal lobe epilepsy (ADLTE). Here, using rat hippocampal neurons in culture, we showed that LGI1 is recruited at the AIS and colocalized with ADAM22 and Kv1 channels. Strikingly, the missense mutations S473L and R474Q of LGI1 identified in ADLTE prevent its association with ADAM22 and enrichment at the AIS. Moreover, we observed that ADAM22 or ADAM23 modulates the trafficking of LGI1, and promotes its ER export and expression at the overall neuronal cell surface. Live-cell imaging indicated that LGI1 is co-transported in axonal vesicles with ADAM22 or ADAM23. Finally, we showed that ADAM22 and ADAM23 also associate with Caspr2 and TAG-1 to be selectively targeted within different axonal sub-regions. So, the combinatorial expression of Kv1-associated CAMs may be critical to tune intrinsic excitability in physiological or epileptogenic context.

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