Small conductance calcium-activated potassium channels (SK channels) are fundamental regulators of neural excitation, important for setting interspike intervals, influencing burst firing patterns, and for their hyperpolarizing role in tonic membrane oscillations. They have been implicated in the disease myotonic muscular dystrophy, linked to memory and learning processes, and their normal expression is important for respiration and parturition. Cloning and heterologous expression of SK channels has allowed characterization of their fundamental properties, and biophysical, molecular biological, biochemical, and crystallographic techniques have proven that calcium gates SK channels entirely by an associated subunit, calmodulin (CaM). Thus the calcium-sensor CaM binds to a domain of approximately 100 residues in the C-terminus of SK, the CaMBD, and transduces its own calcium-induced structural changes to the SK channel, thereby opening and closing the channel. The CaM-CaMBD crystal structure has recently been solved in the presence of calcium, and provides an excellent model for testing how SK channels gate. Since specific interaction sites between CaM and the CaMBD are now known, stabilization of these interactions can distinguish regions of the complex that must move in order for the channels to gate. By determining how SK channels move during gating, insight will be gained into the molecular movements that underlie the function of this important class of ion channel. A fundamental understanding of SK gating has implications for all calcium-gated ion channels, with potential biomedical applications such as the design of drugs which modulate SK gating.
