Known and putative functions of ankyrin G in neurons. (A) Putative scaffolding role at the synapse, where ankyrin G may contribute to the localization of cell adhesion molecules, synaptic receptors, or other synaptic scaffold proteins, as well as to the overall stability of the synapse. (B) Some isoforms of ankyrin G localize to late endosomes and lysosomes where they function in cellular trafficking, thereby directing specific proteins to different subcellular regions. In neurons, cellular trafficking occurs at the pre- and post-synapse of neurons, as well as within the cell body as depicted. (C) Ankyrin G contributes to cellular compartmentalization, helping to distinguish axonal from dendritic processes through the establishment of an axonal barrier at the axon initial segment (AIS) that prevents transport of non-axonal cargo proteins into the axon. (D) Ankyrin G serves as a key scaffold protein at the AIS, interacting with cytoskeletal proteins such as spectrin and actin to localize voltage-gated sodium and potassium channels, cell adhesion molecules (e.g. neurofascin), and GABAergic inhibitory postsynaptic terminals to this region. (E) Similar to its role at the AIS, ankyrin G localizes voltage-gated sodium and potassium channels and cell adhesion molecules to the Nodes of Ranvier, which is mediated through reciprocal interactions with myelin-generating glial cells.