Caspr2, a New Member of the Neurexin Superfamily, Is Localized at the Juxtaparanodes of Myelinated Axons and Associates with K+ Channels

Abstract

Rapid conduction in myelinated axons depends on the generation of specialized subcellular domains to which different sets of ion channels are localized. Here, we describe the identification of Caspr2, a mammalian homolog of Drosophila Neurexin IV (Nrx-IV), and show that this neurexin-like protein and the closely related molecule Caspr/Paranodin demarcate distinct subdomains in myelinated axons. While contactin-associated protein (Caspr) is present at the paranodal junctions, Caspr2 is precisely colocalized with Shaker-like K+ channels in the juxtaparanodal region. We further show that Caspr2 specifically associates with Kv1.1, Kv1.2, and their Kvbeta2 subunit. This association involves the C-terminal sequence of Caspr2, which contains a putative PDZ binding site. These results suggest a role for Caspr family members in the local differentiation of the axon into distinct functional subdomains.

Genome-wide association study with DNA pooling identifies variants at CNTNAP2 associated with pseudoexfoliation syndrome

“…CNTNAP2 is a large gene spanning 2.3 mb of DNA on chromosome 7 and is coding for contactin-associated protein-like 2 (CNTNAP2, also termed Caspr2) a neuronal membrane protein and member of the neurexin superfamily, 36,37 possibly involved in potassium channel trafficking. 36,38 So far it has been suggested as a candidate gene for various neuropsychiatric disorders, [39][40][41][42][43][44][45] however little is known about its specific function and regulation.…”

Shining a light on CNTNAP2: complex functions to complex disorders

“…33,34 Specifically, CASPR2 is a single-pass transmembrane protein, distinguished from most other neurexins by an extracellular discoidin/neuropilin homology domain and a fibrinogen-like region (Figure 1b). 35 These domains mediate cell-cell adhesions and extracellular matrix interactions. 36,37 The large extracellular region of CASPR2 also features four laminin G domains and two epidermal growth factor-like (EGF-like) domains predicted to be involved in receptor-ligand interactions, cell adhesion, migration, and differentiation.…”

“…The most well-defined role for CASPR2 is in the axon initial segment (AIS) and juxtaparanodal regions of myelinated nerves, 35 where it forms a complex with contactin-2 (known as CNTN2 or TAG-1). 63,64 Formation of this complex is mediated by Protein 4.1B binding to the intracellular portion of CASPR2 and is required for the clustering of voltage-gated potassium channels at juxtaparanodes.…”

Autism genetics: searching for specificity and convergence

“…Multiple converging lines of evidence implicate CNTNAP2 in ASD pathology, including its role in a syndromic form of autism [68], variants found in linkage and association studies [35-37], presence of RVs [79], its impact in functional magnetic resonance imaging (MRI) readouts in humans [126], and molecular evidence that its knockout leads to the behavioral manifestation of all three core domains of autism as well as neuronal migration abnormalities [93]. A member of the neurexin superfamily, CNTNAP2 is involved in cell-cell adhesion, clustering of potassium channels at the juxtaparanode [127], neuronal migration, and regulation of GABAergic interneuron numbers [93]. There are data to support an additional contactin family member, CNTN4 , in autism pathophysiology [109,128,129], although this has been recently challenged [130].…”