Molecular Composition

The nodes are characterized by the presence of high density (>1,200/|im2) of Na+ channels that are essential for the generation of the action potential during saltatory conduction (Waxman and Ritchie, 1993). Several other transmembrane and cytoskeletal proteins were also identified at the nodal axolemma: the cell adhesion molecules of the immunoglobulin superfamily (Ig-CAMs) NrCAM and Neurofascin-186 (NF186) (Davis et al., 1996), the cytoskeletal adaptor ankyrinG (Kordeli et al., 1990, 1995), and the actin-binding protein spectrin PIV (Berghs et al., 2000) (Fig. 2A). Recent studies have also revealed the pres

Figure I Schematic structure of myelinated axons. (A) Myelinating glial cells, oligodendrocytes in the CNS, or Schwann cells (SC) in the PNS form the myelin sheath by enwrapping their membrane multiple times around the axon. The myelin covers the axon at intervals (internodes) leaving bare gaps, the nodes of Ranvier. (B) Schematic longitudinal cut of a myelinated fiber around the node of Ranvier showing a heminode. The node, paranode, juxtapara-node (JXP), and internode are labeled. The node is contacted by SC microvilli in the PNS or processes from perinodal astrocytes in the CNS. Myelinated fibers in the PNS are covered by a basal lamina (BL). The paranodal loops form a septate-like junction (SpJ) with the axon. The juxtaparanodal region resides beneath the compact myelin next to the paranode. The internode extends from the juxtaparanodes and lies under the compact myelin. (Modified from Poliak and Peles, 2003.)

Figure I Schematic structure of myelinated axons. (A) Myelinating glial cells, oligodendrocytes in the CNS, or Schwann cells (SC) in the PNS form the myelin sheath by enwrapping their membrane multiple times around the axon. The myelin covers the axon at intervals (internodes) leaving bare gaps, the nodes of Ranvier. (B) Schematic longitudinal cut of a myelinated fiber around the node of Ranvier showing a heminode. The node, paranode, juxtapara-node (JXP), and internode are labeled. The node is contacted by SC microvilli in the PNS or processes from perinodal astrocytes in the CNS. Myelinated fibers in the PNS are covered by a basal lamina (BL). The paranodal loops form a septate-like junction (SpJ) with the axon. The juxtaparanodal region resides beneath the compact myelin next to the paranode. The internode extends from the juxtaparanodes and lies under the compact myelin. (Modified from Poliak and Peles, 2003.)

Figure 2 Molecular composition of the nodal domains. The specialized domains around the node of Ranvier are composed of a distinct set of molecules.

(A) At the nodal axolemma, voltage dependent Na+ channels are anchored to the cytoskeleton by ankyrinG, which also binds NF186, NrCam, and Kv3.1b. AnkyrinG further connects these proteins to the axonal cytoskeleton through PIV-spectrin. In the PNS, Schwann cell microvilli express ERM proteins Dystroglycan (DG), and Syndecan, as well as Gliomedin, which binds to the axolemmal CAMs. The nodal gap also contains several ECM proteins: phosphacan, tenescin, and Bral1.

(B) At the paranodes, Caspr-Contactin complex in the axolemma faces NF155 at the glial membrane. While Contactin alone is able to bind NF155, Caspr inhibits this interaction, suggesting that the Caspr-Contactin complex may bind an as yet unidentified ligand present at the glial loops. The cytoplasmic tail of Caspr interacts with protein 4.1B, providing a potential link with the actin cytoskeleton. (C) At the juxtaparanode's axolemma, voltage-gated K+ channels are found in a macromolecular complex with Caspr2, 4.1B, PSD95, and TAG-1. The latter is also expressed on the glial membrane and binds the axonal Caspr2/TAG-1 complex. Connexin 29, localized at the juxtaparanodal glial membrane could form functional hemichannels. (Modified from Poliak and Peles, 2003.)

Figure 2 Molecular composition of the nodal domains. The specialized domains around the node of Ranvier are composed of a distinct set of molecules.

(A) At the nodal axolemma, voltage dependent Na+ channels are anchored to the cytoskeleton by ankyrinG, which also binds NF186, NrCam, and Kv3.1b. AnkyrinG further connects these proteins to the axonal cytoskeleton through PIV-spectrin. In the PNS, Schwann cell microvilli express ERM proteins Dystroglycan (DG), and Syndecan, as well as Gliomedin, which binds to the axolemmal CAMs. The nodal gap also contains several ECM proteins: phosphacan, tenescin, and Bral1.

(B) At the paranodes, Caspr-Contactin complex in the axolemma faces NF155 at the glial membrane. While Contactin alone is able to bind NF155, Caspr inhibits this interaction, suggesting that the Caspr-Contactin complex may bind an as yet unidentified ligand present at the glial loops. The cytoplasmic tail of Caspr interacts with protein 4.1B, providing a potential link with the actin cytoskeleton. (C) At the juxtaparanode's axolemma, voltage-gated K+ channels are found in a macromolecular complex with Caspr2, 4.1B, PSD95, and TAG-1. The latter is also expressed on the glial membrane and binds the axonal Caspr2/TAG-1 complex. Connexin 29, localized at the juxtaparanodal glial membrane could form functional hemichannels. (Modified from Poliak and Peles, 2003.)

ence of two K+ channels, Kv3.1 (Devaux et al., 2003) and KCNQ2 (Devaux et al., 2004) at the nodes. The nodes are enriched in ankyrinG, a membrane-cytoskeleton adaptor that links integral membrane proteins to the spectrin cytoskele-ton (Kordeli et al., 1990, 1995). AnkyrinG interacts with Na+ channels (Srinivasan et al., 1988), both with their a (Lemaillet et al., 2003) and P (Malhotra et al., 2000) sub-units, as well as with NF186, NrCAM (Garver et al., 1997), and Kv3.1b (Devaux et al., 2003). The P subunit recruits ankyrinG to the plasma membrane (Malhotra et al., 2000), and this interaction is regulated by tyrosine phosphorylation (Malhotra et al., 2002). The binding of ankyrinG to the a subunit is mediated through a sequence of nine amino acids present in all known voltage-gated Na+ channels (Lemaillet et al., 2003). This nine amino acid motif is required for the accumulation of this subunit in the axon initial segment (Garrido et al., 2003), which may be considered as the first node along the axon. AnkyrinG also binds PIV spectrin, a spectrin isoform enriched at the nodes of Ranvier and axon initial segments (Berghs et al., 2000), further anchoring the nodal Na+ channel and Ig-CAMs to the axonal cytoskeleton.

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