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

Abstract

Voltage-gated sodium channels localize at high density in axon initial segments and nodes of Ranvier in myelinated axons. Sodium channels consist of a poreforming ␣ subunit and at least one ␤ subunit. ␤1 is a member of the immunoglobulin superfamily of cell adhesion molecules and interacts homophilically and heterophilically with contactin and Nf186. In this study, we characterized ␤1 interactions with contactin and Nf186 in greater detail and investigated interactions of ␤1 with NrCAM, Nf155, and sodium channel ␤2 and ␤3 subunits. Using Fc fusion proteins and immunocytochemical techniques, we show that ␤1 interacts with the fibronectin-like domains of contactin. ␤1 also interacts with NrCAM, Nf155, sodium channel ␤2, and Nf186 but not with sodium channel ␤3. The interaction of the extracellular domains of ␤1 and ␤2 requires the region 169 TEEEGKTDGEGNA 181 located in the intracellular domain of ␤2. Interaction of ␤1 with Nf186 results in increased Na v 1.2 cell surface density over ␣ alone, similar to that shown previously for contactin and ␤2. We propose that ␤1 is the critical communication link between sodium channels, nodal cell adhesion molecules, and ankyrin G .

Functional reciprocity between Na + channel Na v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

“…5 C and D). Thus, Na v 1.6 expression at the AIS may require clustering of β1 in this region, similar to the CAMs neurofascin-186 and NrCAM, which also are β1-binding partners (37)(38)(39).…”

Postsynaptic Density-93 Clusters Kv1 Channels at Axon Initial Segments Independently of Caspr2

“…Four Na v ␤ subunits have been identified and are members of the immunoglobulin superfamily of CAMs. Both Na v ␤1 and Na v ␤3 can interact with NF-186 and NrCAM (Ratcliffe et al, 2001), but these Na v ␤ subunits do not interact with each other (McEwen and Isom, 2004). It is possible that the distinct channel distributions of Na v channel ␣-subunits may reflect differences in the interactions among Na v ␤ subunits.…”

A Novel Family of Adhesion-Like Molecules That Interacts with the NMDA Receptor

“…Common to both EphB receptors and SALMs are fibronectin type III motifs in their extracellular domains, which may be candidates for interaction with the NR1 subunit. Voltage-gated sodium channels interact directly with members of the Ig superfamily of cell adhesion molecules, including neurofascin, neuron-glia-related cell adhesion molecule, and contactin (Ratcliffe et al, 2001;McEwen and Isom, 2004;Shah et al, 2004), through an Ig loop in the extracellular domain of the ␤ subunit. This interaction is important for regulating the cell surface expression of the channel.…”