Sodium channels are proposed to interact with NrCAM and NF186 via two distinct mechanisms: a direct cis interaction of the β1 channel subunit with NF186 ( Ratcliffe et al., 2001) and indirectly via interactions with ankyrin G, a cytoskeletal scaffold to which nodal CAMs, sodium channels, and their β subunits all bind ( Bennett and Lambert, 1999 Malhotra et al., 2000 McEwen and Isom, 2004). Sodium channels also associate in cis with one or more β subunits ( Ratcliffe et al., 2001), which are likewise concentrated at nodes ( Chen et al., 2002, 2004). Both domains are enriched in voltage-gated sodium channels complexed with the neural cell adhesion molecules (CAMs) NrCAM and the 186-kD isoform of neurofascin (NF Davis et al., 1996). The molecular composition of the AIS and of nodes is remarkably similar ( Poliak and Peles, 2003 Salzer, 2003 Schafer and Rasband, 2006). Thus, initial segments assemble from the inside out driven by the intrinsic accumulation of ankyrin G, whereas PNS nodes assemble from the outside in, specified by Schwann cells, which direct the NF186-dependent recruitment of ankyrin G. NF186 is critical for and initiates PNS node assembly by recruiting ankyrin G, which is required for the localization of sodium channels and the entire nodal complex. In contrast, NF186 is targeted to the node, and independently cleared from the internode, by interactions of its ectodomain with myelinating Schwann cells. The AIS is intrinsically specified it forms independent of NF186, which is targeted to this site via intracellular interactions that require ankyrin G. We show that the AIS and peripheral nervous system (PNS) nodes both require ankyrin G but assemble by distinct mechanisms. Both domains are enriched in sodium channels complexed with adhesion molecules (neurofascin 186 and NrCAM) and cytoskeletal proteins (ankyrin G and βIV spectrin). Axon initial segments (AISs) and nodes of Ranvier are sites of action potential generation and propagation, respectively.
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