Cytoskeletal scaffolding of NaVs and KVs in neocortical pyramidal neurons: Implications for neuronal signaling and plasticity

The initiation and propagation of action potentials (APs) depend on the precise localization of voltage-gated sodium (NaV) and potassium (KV) channels in neurons. In neocortical pyramidal neurons, NaV1.2 and NaV1.6 are key at the axon initial segment (AIS) and nodes of Ranvier (noR), driving AP initiation and propagation. NaV1.2 also supports AP backpropagation in the soma and dendrites. Ankyrin-G anchors these channels at the AIS and noR, while new findings reveal that ankyrin-B scaffolds NaV1.2 in dendrites. This review highlights how ankyrins stabilize NaV and KV channels across neuronal domains, ensuring proper function crucial for excitability, synaptic plasticity, and signaling. Recent findings explore how ankyrins differentially localize NaV1.2 and NaV1.6, with implications for understanding neurological disorders linked to disrupted channel localization.