ankyrin3

Ankyrin-3, commonly known as ankyrin-G, is a member of the ankyrin family of adaptor proteins encoded by the ANK3 gene in humans. It functions as a cytoskeletal linker that couples integral membrane proteins to the spectrin-based cytoskeleton, thereby helping to organize and stabilize specialized membrane domains. The ANK3 gene produces multiple isoforms through alternative splicing, including ubiquitous smaller forms and neuron-specific giant isoforms that reach several hundred kilodaltons.

In neurons, ankyrin-3/G is enriched at the axon initial segment and nodes of Ranvier, where it orchestrates a complex membrane scaffold essential for electrical signaling. It binds and clusters voltage-gated sodium channels, particularly Nav1.2 and Nav1.6, together with other components such as βIV-spectrin and neurofascin. This clustering supports proper neuronal polarity and action potential initiation. Ankyrin-3 also participates in stabilizing various other membrane proteins and influences trafficking and localization of channel complexes.

Structure and expression: ankyrin-3 contains an N-terminal ankyrin-repeat domain, a central spectrin-binding domain, and a C-terminal regulatory region; isoforms differ in their regulatory segments, contributing to distinct tissue distributions. While giant neuronal isoforms predominate in the nervous system, smaller isoforms are more widely expressed in other tissues, including the heart and peripheral tissues.

Clinical significance: genetic variation in ANK3 has been associated with several neuropsychiatric conditions in association studies, notably bipolar disorder, with additional links to schizophrenia and autism reported in some studies. The exact functional consequences are not fully understood, but alterations in ankyrin-3 can affect AIS integrity, neuronal excitability, and protein trafficking in neurons.