Project abstract for group fohlmeis

Multi-Dimensional (1-6D) Kinetics of Voltage-Gated Ion Channels in Central Neurons

Voltage-gating kinetic schemes for sodium- and potassium-channels for nerve (and muscle) are being developed in which every conformational state (of gating) is individually recognized. Almost all species of Na- and K-channels appear to be structurally similar in that their primary, “alpha,” subunits are composed of four or five similar repeat sequences in a single protein molecule, in conjunction with smaller and molecularly distinct "beta" polypeptide subunits. Currently, highly simplified parallel and sequential kinetic schemes treat many of the subunits and transition paths as interchangeable, thus severely restricting detailed analysis. This research, in contrast, employs higher-dimensional geometries (4-, 5-, and 6-D cubes) as the basis for the kinetic diagrams (cube-corners = individual kinetic states, edges = kinetic transition paths). This treats every possible individual kinetic state (molecular conformation) and path in the channel gating mechanism as unique. The results are expected to yield fundamental advances in ion channel gating (e.g., evaluating the robustness of the basic channel-structural design and subunit strategy), as well as detailed effects of specific channel mutations. Ion channel subtypes NaV1.1, 1.2, 1.3, 1.6, and Kv1.1 through 1.6 specifically will be evaluated. MSI resources areemployed for large-scale computation and graphics representation in the higher dimensional kinetic regimes.