Contactin Associates with Na⁺Channels and Increases Their Functional Expression

Abstract

Contactin (also known as F3, F11) is a surface glycoprotein that has significant homology with the beta2 subunit of voltage-gated Na(+) channels. Contactin and Na(+) channels can be reciprocally coimmunoprecipitated from brain homogenates, indicating association within a complex. Cells cotransfected with Na(+) channel Na(v)1.2alpha and beta1 subunits and contactin have threefold to fourfold higher peak Na(+) currents than cells with Na(v)1.2alpha alone, Na(v)1.2/beta1, Na(v)1.2/contactin, or Na(v)1.2/beta1/beta2. These cells also have a correspondingly higher saxitoxin binding, suggesting an increased Na(+) channel surface membrane density. Coimmunoprecipitation of different subunits from cell lines shows that contactin interacts specifically with the beta1 subunit. In the PNS, immunocytochemical studies show a transient colocalization of contactin and Na(+) channels at new nodes of Ranvier forming during remyelination. In the CNS, there is a particularly high level of colocalization of Na(+) channels and contactin at nodes both during development and in the adult. Contactin may thus significantly influence the functional expression and distribution of Na(+) channels in neurons.

Heterophilic Interactions of Sodium Channel β1 Subunits with Axonal and Glial Cell Adhesion Molecules

“…Sodium channels are clustered at high density in axon initial segments and nodes of Ranvier of myelinated axons, where they co-localize with members of the Ig superfamily of CAMs such as contactin, NrCAM, and neurofascin 186 (Nf186) (2,17,18).…”

“…␤1 and ␤2 colocalize with sodium channel ␣ subunits at nodes of Ranvier, and ␤1 interacts with contactin and with Nf186 in vitro (9,17,19,20). Nf186, Nr-CAM, ␤1, and ␤2 each interact in vitro with a key cytoskeletal anchoring protein, ankyrin G , that is also localized to nodes of Ranvier (21)(22)(23).…”

Modulation of the Cardiac Sodium Channel Nav1.5 by Fibroblast Growth Factor Homologous Factor 1B

“…Auxiliary ␤-subunits affect the assembly, trafficking, and electrophysiological activities of ␣-subunits (6) and have recently been shown to link sodium channels to extracellular matrix proteins via their association with neurofascin (7). The neuronal adhesion molecule contactin/F3 increases the membrane insertion of sodium channels by direct (8) or indirect (9) association with the ␣-subunit of the channels. The association with contactin/F3 may also mediate the interaction of the channel with the extracellular protein tenascin (8).…”

Abnormal myelination in the spinal cord of PTPα-knockout mice

“…13,14 F3 is the first GPI-linked molecule identified that is located in both nodal and paranodal regions. 15,16 It forms an intracellular complex with paranodin, a single transmembrane protein 17 also termed Caspr and modulates its transfer from the endomembrane system to the axolemma. 15,18 F3 also is clustered at the paranode, a critical site of axoglial dialog for initiating myelination, from the first postnatal week.…”

“…15,18 F3 also is clustered at the paranode, a critical site of axoglial dialog for initiating myelination, from the first postnatal week. 16 PTPα interacts with F3 to form a membrane-spanning co-receptor complex, which potentially transduces extracellular signals. 7 Similar to F3, PTPα is expressed by both neuron and oligodendrocytes in the CNS.…”