SK_Ca 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 SK_Ca 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 SK_Ca 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 SK_Ca 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 SK_Ca channels, we overexpressed K_Ca2.1 (SK1) and K_Ca2.2 (SK2), the predominant SK_Ca subunits expressed in the cortex, in pyramidal cells of cultured brain slices. Overexpression of K_Ca2.1 and K_Ca2.2 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 SK_Ca subunit (SK3-1B) capable of acting as a dominant negative for the entire family of SK _Ca-IK_Ca 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 SK _Ca channels mediate I_sAHP in pyramidal cells and indicate that a different potassium channel mediates this current.