Control of electrical activity in central neurons by modulating the gatingof small conductance Ca2+-activated K+ channels

In most central neurons, action potentials are followed by an afterhyperpol arization (AHP) that controls firing pattern and excitability, The medium a nd slow components of the AHP have been ascribed to the activation of small conductance Ca2+-activated potassium (SK) channels. Cloned SK channels are heteromeric complexes of SK alpha -subunits and calmodulin, The channels a re activated by Ca2+ binding to calmodulin that induces conformational chan ges resulting in channel opening, and channel deactivation is the reverse p rocess brought about by dissociation of Ca2+ Rom calmodulin, Here we show t hat SK channel gating is effectively modulated by 1-ethyl-2-benzimidazolino ne (EBIO). Application of EBIO to cloned SK channels shifts the Ca2+ concen tration-response relation into the lower nanomolar range and slows channel deactivation by almost 10-fold. In hippocampal CA1 neurons, EBIO increased both the medium and slow AHP, strongly reducing electrical activity. Moreov er, EBIO suppressed the hyperexcitability induced by low Mg2+ in cultured c ortical neurons. These results underscore the importance of SK channels for shaping the electrical response patterns of central neurons and suggest th at modulating SK channel gating is a potent mechanism for controlling excit ability in the central nervous system.