Abstract
Voltage-gated sodium channels isolated from mammalian brain are composed of α, β1, and β2 subunits. The α subunit forms the ion conducting pore of the channel, whereas the β1 and β2 subunits modulate channel function, as well as channel plasma membrane expression levels. β1 and β2 each contain a single, extracellular Ig-like domain with structural similarity to the neural cell adhesion molecule (CAM), myelin Po. β2 contains strong amino acid homology to the third Ig domain and to the juxtamembrane region of F3/contactin. Many CAMs of the Ig superfamily have been shown to interact with extracellular matrix molecules. We hypothesized that β2 may interact with tenascin-R (TN-R), an extracellular matrix molecule that is secreted by oligodendrocytes during myelination and that binds F3-contactin. We show here that cells expressing sodium channel β1 or β2 subunits are functionally modulated by TN-R. Transfected cells stably expressing β1 or β2 subunits initially recognized and then were repelled from TN-R substrates. The cysteine-rich amino-terminal domain of TN-R expressed as a recombinant peptide, termed EGF-L, appears to be responsible for the repellent effect on β subunit-expressing cells. The epidermal growth factor-like repeats and fibronectin-like repeats 6–8 are most effective in the initial adhesion of β subunit-expressing cells. Application of EGF-L to αIIAβ1β2 channels expressed in Xenopus oocytes potentiated expressed sodium currents without significantly altering current time course or the voltage dependence of current activation or inactivation. Thus, sodium channel β subunits appear to function as CAMs, and TN-R may be an important regulator of sodium channel localization and function in neurons.