Schwannomin-Interacting Protein-1 Isoform IQCJ-SCHIP-1 Is a Late Component of Nodes of Ranvier and Axon Initial Segments

Abstract

Axon initial segments (AISs) and nodes of Ranvier (NRs) are essential regions for saltatory conduction of the action potential along the axon. These two domains are enriched in similar multimolecular complexes, which include voltage-gated sodium channels (Na v ), NF186 (neurofascin 186), NrCAM (neuron glia-related cell adhesion molecule), and cytoskeleton linkers ankyrin G (AnkG) and ␤IV-spectrin. Identification of novel members of these complexes is critical to better understand their formation, function, and maintenance. Here we report that IQCJ-SCHIP-1, a recently identified isoform of schwannomin-interacting protein-1 (SCHIP-1), is a novel component of both AISs and NRs in the central and peripheral nervous systems. We show that IQCJ-SCHIP-1 binds calmodulin in the absence of Ca 2ϩ and is highly enriched at AISs and NRs. IQCJ-SCHIP-1 accumulation at AISs and NRs is a late event, suggesting that IQCJ-SCHIP-1 is likely to play a role in mature AISs and NRs rather than during their formation. IQCJ-SCHIP-1 was not detected at

The cytoskeleton-associated protein SCHIP1 is involved in axon guidance, and is required for piriform cortex and anterior commissure development

“…Spontaneous neuronal activity was proposed to stimulate axon growth (Mire et al, 2012). The IQCJ-SCHIP1 isoform is a late component of the axon initial segment and could therefore play a role in controlling the excitability of mature neurons (Martin et al, 2008). However, this is unlikely to be the case in our in vitro experiments since we analyzed axon outgrowth at stages at which the axon initial segments have not yet formed (data not shown), hence suggesting earlier functions of SCHIP1 during axon development.…”

“…All isoforms differ in their N-terminus and share a C-terminal domain encoded by exons 9 to 14. This domain includes a ∼40 residue leucine zipper that is predicted to adopt a coiled-coil conformation and is required for ankyrin and schwannomin binding (Goutebroze et al, 2000;Martin et al, 2008). Mutant mice were generated by deletion of Schip1 exon 10, which is predicted to result in a frameshift that creates a STOP codon in exon 11 (supplementary material Fig.…”

“…Schwannomin-interacting protein 1 (SCHIP1) is a cytoplasmic protein identified as a partner of the tumor suppressor protein schwannomin [also known as merlin or neurofibromatosis 2 (NF2)] (Goutebroze et al, 2000). The IQCJ-SCHIP1 isoform is a component of axon initial segments and nodes of Ranvier, two regions highly enriched in Na v channels important for the initiation and the saltatory conduction of action potentials, respectively (Martin et al, 2008). In these regions, Na v channels sit in multimolecular complexes comprising KCNQ channels and cell adhesion molecules (CAMs), NRCAM and neurofascin, anchored to the actin cytoskeleton through their interaction with the ankyrin G / βIV spectrin-based cortical cytoskeleton (Buttermore et al, 2013).…”

“…In these regions, Na v channels sit in multimolecular complexes comprising KCNQ channels and cell adhesion molecules (CAMs), NRCAM and neurofascin, anchored to the actin cytoskeleton through their interaction with the ankyrin G / βIV spectrin-based cortical cytoskeleton (Buttermore et al, 2013). In this complex, SCHIP1 interacts directly with ankyrin G (also known as ankyrin 3) (Martin et al, 2008). SCHIP1 is also able to interact with ankyrin B (also known as ankyrin 2), which binds adhesion molecules involved in axon formation (Bennett and Lorenzo, 2013).…”

Voltage-gated sodium channel organization in neurons: Protein interactions and trafficking pathways

“…1B). The AIS and the nodes of Ranvier are also enriched in other proteins, such as protein kinase casein kinase 2 (CK2) which regulates ion channel interaction with ankG [9], SCHIP-1 isoforms [55], FHF2 and FHF4, two members of the fibroblast growth factor homologous factors (FHFs, [32]) and members of the NFB signaling pathway [66,77]. Lastly, in certain neuronal types, members of the Kv1 voltage-gated potassium channel family are restricted to the distal part of the AIS [39,52].…”