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 pore-forming α subunit and at least one β subunit. β1 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 β1 interactions with contactin and Nf186 in greater detail and investigated interactions of β1 with NrCAM, Nf155, and sodium channel β2 and β3 subunits. Using Fc fusion proteins and immunocytochemical techniques, we show that β1 interacts with the fibronectin-like domains of contactin. β1 also interacts with NrCAM, Nf155, sodium channel β2, and Nf186 but not with sodium channel β3. The interaction of the extracellular domains of β1 and β2 requires the region 169TEEEGKTDGEGNA181 located in the intracellular domain of β2. Interaction of β1 with Nf186 results in increased Nav1.2 cell surface density over α alone, similar to that shown previously for contactin and β2. We propose that β1 is the critical communication link between sodium channels, nodal cell adhesion molecules, and ankyrinG.