Tenascin-R is a functional modulator of sodium channel β subunits

Voltage-gated sodium channels isolated from mammalian brain are composed of a, beta 1 and beta 2 subunits, The cu subunit forms the ion conducting pore of the channel, whereas the beta 1 and beta 2 subunits modulate channel function, as well as channel plasma membrane expression levels, beta 1 and beta 2 each contain a single, extracellular Ig-like domain with structural similarity to the neural cell adhesion molecule (CAM), myelin Po. beta 2 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 beta 2 may interact with tenascin-alpha (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 beta 1 or beta 2 subunits are functionally modulated by TN-R, Transfected cells stably expressing beta 1 or beta 2 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 beta subunit-expressing cells. The epidermal growth factor-like repeats and fibronectin-like repeats 6-8 are most effective in the initial adhesion of id subunit-expressing cells. Application of EGF-L to alpha IIA beta 1 beta 2 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 beta subunits appear to function as CAMs, and TN-R may be an important regulator of sodium channel localization and function in neurons.