Heterophilic interactions of sodium channel β1 subunits with axonal and glial cell adhesion molecules

Voltage-gated sodium channels localize at high density in axon initial segments and nodes of Ranvier in myelinated axons. Sodium channels consist of a pore-forming alpha subunit and at least one beta subunit. beta1 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 beta1 interactions with contactin and Nf186 in greater detail and investigated interactions of beta1 with NrCAM, Nf155, and sodium channel beta2 and beta3 subunits. Using Fc fusion proteins and immunocytochemical techniques, we show that beta1 interacts with the fibronectin-like domains of contactin. beta1 also interacts with NrCAM, Nf155, sodium channel beta2, and Nf186 but not with sodium channel beta3. The interaction of the extracellular domains of beta1 and beta2 requires the region (169)TEEEGKTDGEGNA(181) located in the intracellular domain of beta2. Interaction of beta1 with Nf186 results in increased Na(v)1.2 cell surface density over alpha alone, similar to that shown previously for contactin and beta2. We propose that beta1 is the critical communication link between sodium channels, nodal cell adhesion molecules, and ankyrin(G).