In neurones, voltage-gated sodium (Nav) channels initiate the action potential. Sodium channels consist of a ~ 250 kDa alpha-subunit and ~40 kDa beta-subunits. The beta-subunits modulate channel gating. The Nav beta-subunits possess an extracellular immunoglobulin (Ig) domain, connected to an alpha-helical transmembrane domain and an intracellular carboxy-terminal region. We study the structure and function of the Nav channel beta 3-subunit. We determined the structure of the beta 3-subunit Ig domain using X-ray crystallography. We have shown that the beta3-subunits trimerise via their Ig domains, and cross-link Nav channel alpha-subunits. These results provide a new interpretation of previous electrophysiological data, and raise new questions. Does Nav channel cross-linking by beta 3 lead to functionally coupled channels? Can different Nav alpha-subunit isoforms be cross-linked together? Do beta-subunits stabilise Nav channels into larger protein clusters on the plasma membrane?
