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

Dyke P Mcewen,Lori L Isom

doi:10.1074/jbc.m405990200

Dyke P Mcewen, Lori L Isom

Open Access

https://doi.org/10.1074/jbc.m405990200

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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 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 169TEEEGKTDGEGNA181 located in the intracellular domain of beta2. Interaction of beta1 with Nf186 results in increased Nav).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 ankyrinG.

Highlights

The axo-glial complex in myelinated axons is composed of a nodal gap region that contains high density clusters of voltagegated sodium channels and a juxtaparanodal region that contains voltage-gated potassium channels [1,2,3,4,5,6]
Using Fc fusion proteins and immunocytochemical techniques, we show that ␤1 interacts with the fibronectin-like domains of contactin. ␤1 interacts with NrCAM, neurofascin 155 (Nf155), sodium channel ␤2, and neurofascin 186 (Nf186) but not with sodium channel ␤3
Contactin is expressed at paranodes in the peripheral nervous system (PNS), where it interacts with Caspr on the axonal membrane and neurofascin 155 (Nf155) on the Schwann cell membrane to form septatelike junctions that separate the nodal gap from the juxtaparanode [31,32,33]

Summary

Introduction

The axo-glial complex in myelinated axons is composed of a nodal gap region that contains high density clusters of voltagegated sodium channels and a juxtaparanodal region that contains voltage-gated potassium channels [1,2,3,4,5,6]. The nodal gap and the juxtaparanode are separated by the paranode, a region containing septate-like junctions composed of cell adhesion molecules (CAMs) that act as diffusion barriers to ion channel movement (2, 6 – 8). This specific arrangement of voltage-gated sodium and potassium channels results in rapid and efficient saltatory conduction of action potentials (9 –12). In optic nerve, developing nodes of Ranvier are defined by clustering of ankyinG prior to the arrival of CAMs and sodium channels [28, 29], and this process is independent of paranodal axoglial cell adhesion [29]. The number of mature nodes of Ranvier is significantly reduced in ␤1 (Ϫ/Ϫ) optic nerves, and we have proposed that the loss of sodium channel-contactin interactions at the node may be responsible for this effect [9]

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