Small conductance Ca2+-activated K+ channels (SK channels) contribute to the long lasting afterhyperpolarization (AHP) that follows an action potential in many central neurons. The biophysical and pharmacological attributes of cloned SK channels strongly suggest that one or more of them underlie the medium component of the AHP that regulates interspike interval and plays an important role in setting tonic firing frequency. The cloned SK channels comprised a distinct subfamily of K+ channels. Heterologously expressed SK channels recapitulate the biophysical and pharmacological hallmarks of native SK channels, being gated solely by intracellular Ca2+ ions with no voltage- dependence to their gating, small unitary conductance values, and sensitivity to the bee venom peptide toxin, apamin. Molecular, biochemical and electrohpysiological studies have revealed that CA2+-gating in SK channels is due to heteromeric assembly of the SK ? pore-forming subunits with calmodulin (CaM). Ca2+-binding to the N- terminal E-F hands of CaM is responsible for SK channel gating. Crystalographic studies suggest that SK channels gate as a dimer-of-dimers, and that the physical gate of SK channels resides at or near the selectivity filter of the channels. In addition, Ca2+-independent interactions between the SK channel ? subunits and CaM are necessary for proper membrane trafficking.