SKCa channels mediate the medium but not the slow calcium-activated afterhyperpolarization in cortical neurons

Many neurons, including pyramidal cells of the cortex, express a slow afterhyperpolarization (sAHP) that regulates their firing. Although initial findings suggested that the current underlying the sAHP could be carried through SKCa channels, recent work has uncovered anomalies that are not congruent with this idea. Here, we used overexpression and dominant-negative strategies to assess the involvement of SKCa channels in mediating the current underlying the sAHP in pyramidal cells of the cerebral cortex. Pyramidal cells of layer V exhibit robust AHP currents composed of two kinetically and pharmacologically distinguishable currents known as the medium AHP current (I-mAHP) and the slow AHP current (I-sAHP). I-mAHP is blocked by the SKCa channel blockers apamin and bicuculline, whereas I-sAHP is resistant to these agents but is inhibited by activation of muscarinic receptors. To test for a role for SKCa channels, we overexpressed K(Ca)2.1 (SK1) and K(Ca)2.2 (SK2), the predominant SKCa subunits expressed in the cortex, in pyramidal cells of cultured brain slices. Overexpression of K(Ca)2.1 and K(Ca)2.2 resulted in a fourfold to fivefold increase in the amplitude of I-mAHP but had no detectable effect on I-sAHP. As an additional test, we examined I-sAHP in a transgenic mouse expressing a truncated SKCa subunit (SK3-1B) capable of acting as a dominant negative for the entire family of SKCa-IKCa channels. Expression of SK3-1B profoundly inhibited I-mAHP but again had no discernable effect on I-sAHP. These results are inconsistent with the proposal that SKCa channels mediate I-sAHP in pyramidal cells and indicate that a different potassium channel mediates this current.