8). Interestingly, the mechanisms responsible for clustering ion channels at axonal domains evolved before myelination (Hill et al., 2008). By way of example, the structural amino acid motif in sodium channels that permits them to hyperlink towards the actin pectrin cytoskeleton via AnkG evolved in early chordates, allowing for the clustering of sodium channels at the AIS before nodes evolved (Lemaillet et al., 2003; Hill et al., 2008; Rasband, 2008). In addition, this AnkG binding motif can also be conserved in potassium channels that localize to the AIS and node (Pan et al., 2006; Rasband, 2008). Nevertheless, the potassium channel motif evolved concurrently with myelination, because potassium channels are needed for suitable saltatory conduction (Hill et al., 2008). Importantly, nodes are certainly not discovered in invertebrate nervous systems, but equivalent structures do exist for the AIS, as in vertebrates. On the other hand, the action possible initiation web site in invertebrate axons occurs at variable distances in the soma, and a single neurite can split into each axon and dendrite distally in the soma (Meyrand et al., 1992; Rolls et al., 2007; Maniar et al., 2012). Interestingly, axonal domains in C. elegans are analogous for the vertebrate AIS, which includes the clustering of AnkG and microtubule-stabilizing protein UNC-33, that is the C. elegans protein collapsin response mediator protein-2 (CRMP-2; Maniar et al., 2012). In vertebrates CRMP-2 is essential for axon specification (Inagaki et al.4-Tetrahydrothiopyranone 1,1-dioxide Data Sheet , 2001; Fukata et al., 2002; Maniar et al., 2012). Hence, the mechanisms accountable for sodium channel clustering and axonal organization seem to become conserved throughout evolution. Along with evolutionarily conserved motifs on AIS and nodal ion channels, the paranodal AGSJs are also hugely conserved all through evolution (Banerjee et al., 2006). Septate junctions are prominent within the epithelia and nervous method of invertebrates but are found only in the vertebrate AGSJs (Banerjee et al., 2006). Importantly, the 3 main elements on the AGSJs are very conserved in invertebrates, for instance in Drosophila, in which orthologs for Caspr/Cont/NfascNF155 are neurexin IV/Cont/neuroglian (Banerjee et al., 2006). Additionally, neurexin IV includes a 4.1-binding sequence in its C-terminus (Bhat, 2003; Banerjee et al., 2006), along with the 4.1 household ortholog coracle colocalizes with neurexin IV at septate junctions (Fehon et al., 1994). Comparison among mutational studies in vertebrates and invertebrates revealed a frequent mechanism whereby the junctions are stabilized by way of their interaction with 4.1308298-23-8 Chemscene 1 proteins towards the underlying cytoskeleton (Fehon et al.PMID:35670838 , 1994; Lamb et al., 1998; Ward et al., 1998; Horresh et al., 2010; Buttermore et al., 2011). The conserved functions of septate junctions and ion channel clustering across evolution reinforce the importance of axonal domain organization for maintenance of neuronal function. Thus, greater expertise of how the molecular processes and interactions lead to organization and upkeep with the AIS, node, paranode, JXP and internode, will open possibilities to design therapeutic techniques to treat and/or stop the problems that target these domains. Also, a much better understanding of how the molecular fences and barriers are established along the axon and how they may be maintained for the entire life of the organismNIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptJ Neurosci Res. Author manuscript; out there in PMC 2014 June 09.Butt.