The distribution of the voltage-gated Kv1 K + channels at the axon initial segment (AIS) influences neuronal intrinsic excitability. The Kv1.1 and Kv1.2 (also known as KCNA1 and KCNA2, respectively) subunits are associated with cell adhesion molecules (CAMs), including Caspr2 (also known as CNTNAP2) and LGI1, which 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, by using rat hippocampal neurons in culture, we showed that LGI1 is recruited to the AIS where it colocalizes 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 and ADAM23 modulate the trafficking of LGI1, and promote 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 and ADAM23. Finally, we showed that ADAM22 and ADAM23 also associate with Caspr2 and TAG-1 (also known as CNTN2) to be selectively targeted to different axonal sub-regions. Hence, the combinatorial expression of Kv1-associated CAMs may be critical to tune intrinsic excitability in physiological and epileptogenic contexts.
The distribution of voltage-gated potassium channels Kv1 at the axon initial segment (AIS), along the axon and at presynaptic terminals influences intrinsic excitability and transmitter release. 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 (ADTLE). In the present study, we used rat hippocampal neurons in culture to assess whether interplay between distinct Kv1-associated CAMs contributes to targeting at the AIS. Strikingly, LGI1 was highly restricted to the AIS surface when transfected alone, whereas the missense mutant LGI1 S473L associated with ADLTE was not. Next, we showed that ADAM22 and ADAM23 acted as chaperones to promote axonal vesicular transport ofLGI1 reducing its density at the AIS. Moreover, live-cell imaging of fluorescently labelled CAMs indicated that LGI1 was 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. The combinatorial expression of Kv1-associated CAMs may be critical to tune intrinsic excitability in a physiological or an epileptogenic context.
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