Tenascin-R is a functional modulator of sodium channel beta 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 por e of the channel, whereas the beta 1 and beta 2 subunits modulate channel f unction, as well as channel plasma membrane expression levels, beta 1 and b eta 2 each contain a single, extracellular Ig-like domain with structural s imilarity to the neural cell adhesion molecule (CAM), myelin Po. beta 2 con tains strong amino acid homology to the third Ig domain and to the juxtamem brane region of F3/contactin. Many CAMs of the Ig superfamily have been sho wn to interact with extracellular matrix molecules. We hypothesized that be ta 2 may interact with tenascin-alpha (TN-R), an extracellular matrix molec ule that is secreted by oligodendrocytes during myelination and that binds F3-contactin. We show here that cells expressing sodium channel beta 1 or b eta 2 subunits are functionally modulated by TN-R, Transfected cells stably expressing beta 1 or beta 2 subunits initially recognized and then were re pelled from TN-R substrates, The cysteine-rich amino-terminal domain of TN- R expressed as a recombinant peptide, termed EGF-L, appears to be responsib le for the repellent effect on beta subunit-expressing cells. The epidermal growth factor-like repeats and fibronectin-like repeats 6-8 are most effec tive 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 pot entiated expressed sodium currents without significantly altering current t ime course or the voltage dependence of current activation or inactivation. Thus, sodium channel beta subunits appear to function as CAMs, and TN-R ma y be an important regulator of sodium channel localization and function in neurons.