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

Abstract

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.

Adiposity‐related insulin resistance and thickness of the cerebral cortex in middle‐aged adults

“…[27][28][29][30] Oligodendrocytes form myelin ensheathment around neuronal axons. 42 Myelin ends attach to axons in paranode and juxta-paranode regions, which include voltage-gated potassium channels critical for regulating membrane potential, and thus signal transduction along the axons, 42 as well as neurone excitability (when at the axon initial segment 43 ). Whether adiposity/IR inhibits oligodendrocyte production of myelin, thus diminishing the ensheathment of axon and impacting membrane potential and axon integrity, requires further study; however, it may contribute to lower cortical thickness.…”

Global ribosome profiling reveals that mutant huntingtin stalls ribosomes and represses protein synthesis independent of fragile X mental retardation protein

“…3, H and I). In the HDhet cells, for example, Adam22, a catalytically inactive member of transmembrane ADAM metalloproteases linked to synaptic functions (40), was paused at position 1967 (ACG) ( fig. S7A).…”

Selective Axonal Expression of the Kv1 Channel Complex in Pre-myelinated GABAergic Hippocampal Neurons

“…Since protein 4.1B is known to bind the cytoplasmic tail of Caspr2 and is required for the recruitment of the juxtaparanodal complex in myelinated fibers, we also analyzed its distribution and found that it was present along the distal axon and faintly expressed at the AIS of inhibitory neurons (Figure 5C,G). Similarly to TAG-1 and Caspr2, ADAM22, another CAM associated with the Kv1 complex at the AIS (Ogawa et al, 2008; Hivert et al, 2019) was found to be preferentially expressed all along inhibitory axons in mature cultured hippocampal neurons (Figure 5D). ADAM22 appeared to be enriched at the AIS of inhibitory neurons, in a manner similar to TAG-1 (Figure 5D, red arrows).…”

“…Our data suggest that TAG-1 may be associated with ADAM22 at the AIS and also along the axon. Indeed, we recently reported that TAG-1 can be associated with ADAM22 using co-immunoprecipitation experiments and that the two CAMs are sorted together in axonal transport vesicles (Hivert et al, 2019). However, the persistence of Kv1.2 subunits along the axons in TAG-1- and protein 4.1B-deficient cells reveals that the Caspr2/TAG-1/4.1B complex may be dispensable for the distal distribution of Kv1 channels.…”