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

In most central neurons, action potentials are fol- lowed by an afterhyperpolarization (AHP) that controls firing pattern and excitability. The medium and slow components of the AHP have been ascribed to the acti- vation of small conductance Ca2ⴙ-activated potassium (SK) channels. Cloned SK channels are heteromeric complexes of SK ␣-subunits and calmodulin. The chan- nels are activated by Ca2ⴙ binding to calmodulin that induces conformational changes resulting in channel opening, and channel deactivation is the reverse proc- ess brought about by dissociation of Ca2ⴙ from calmod- ulin. Here we show that SK channel gating is effectively modulated by 1-ethyl-2-benzimidazolinone (EBIO). Ap- plication of EBIO to cloned SK channels shifts the Ca2ⴙ concentration-response relation into the lower nanomo- lar 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. Moreover, EBIO suppressed the hyperexcitabil- ity induced by low Mg2ⴙ in cultured cortical neurons. These results underscore the importance ofSK channels for shaping the electrical response patterns of central neurons and suggest that modulating SK channel gating is a potent mechanism for controlling excitability in the central nervous system.