Sodium channel β1 and β3 subunits associate with neurofascin through their extracellular immunoglobulin-like domain

Abstract

Sequence homology predicts that the extracellular domain of the sodium channel β1 subunit forms an immunoglobulin (Ig) fold and functions as a cell adhesion molecule. We show here that β1 subunits associate with neurofascin, a neuronal cell adhesion molecule that plays a key role in the assembly of nodes of Ranvier. The first Ig-like domain and second fibronectin type III–like domain of neurofascin mediate the interaction with the extracellular Ig-like domain of β1, confirming the proposed function of this domain as a cell adhesion molecule. β1 subunits localize to nodes of Ranvier with neurofascin in sciatic nerve axons, and β1 and neurofascin are associated as early as postnatal day 5, during the period that nodes of Ranvier are forming. This association of β1 subunit extracellular domains with neurofascin in developing axons may facilitate recruitment and concentration of sodium channel complexes at nodes of Ranvier.

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

“…A polyclonal anti-␤3 antibody was a gift from Dr. William A. Catterall (University of Washington, Seattle, WA) and has been described previously (20). Cy3-conjugated anti-human-Fc antibodies were obtained from Jackson ImmunoResearch Laboratories (West Grove, PA).…”

“…Previous studies have shown that Nf186 is important for determining node of Ranvier location (2, 18). Ratcliffe et al (20) showed that the extracellular domain of ␤1 interacts with Nf186 in a heterologous system using coimmunoprecipitation techniques. As shown in Fig.…”

“…␤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.…”

Voltage-gated Ion Channels

“…They comprise a single Sodium channel auxiliary subunits, Na 1 to Na 4, interact with the different subunits and alter their physiological properties and V β V β α subcellular localization. These proteins have a single transmembrane segment, a large N-terminal extracellular domain that is homologous in structure to a variable chain (V-type) immunoglobulin-like fold, and a short C-terminal intracellular segment ( ) ( with an extracellular Ig-fold, they also serve as cell adhesion molecules by interacting with extracellular matrix proteins, cell adhesion molecules, and cytoskeletal linker proteins ( ; ; ; Ratcliffe et al, 2000Srinivasan et al, 1998Ratcliffe et al, 2001 ). The Na subunits are a recent evolutionary addition to the family of ion channel associated proteins, as Malhotra et al, 2002 V β they have only been identified in vertebrates.…”