Contactin-associated protein 2 (Caspr2) is a member of the neurexin superfamily, a group of transmembrane proteins that mediate cell–to-cell interactions in the nervous system^1,2.

Neurexins are adhesion molecules expressed mainly at presynaptic locations that form trans-synaptic cell–to-cell adhesion complexes via binding to their postsynaptic partners, the neuroligins².

Caspr2, like other neurexin proteins, is a type I membrane protein that contains epidermal growth factor repeats, laminin G domains, an F5/8 type C domain, and fibrinogen-like domains in its extracellular domain^1,2.

Caspr2 is localized at the juxtaparanodes of myelinated axons, a specialized region that mediates interactions between neurons and glia during nervous system development¹.

The juxtaparanodal region is highly enriched with heteromultimers of the K⁺ channels K_V1.1, K_V1.2, and their cytoplasmic K_Vβ2 subunit, which may help in axon conduction stabilization and the maintenance of the internodal resting potential¹. Caspr2 is essential for the targeted localization of these channels in the juxtaparanodal regions. Indeed, targeted disruption of Caspr2 resulted in a marked reduction in the accumulation of K⁺ channels at the juxtaparanodes in both peripheral and central nervous system axons³.

Moreover, mutations in the Caspr2 gene have been implicated in multiple neurodevelopmental disorders, including Tourette syndrome, schizophrenia, epilepsy, autism, attention-deficit hyperactivity disorder and mental retardation^4-6.