SKCaChannels Mediate the Medium But Not the Slow Calcium-Activated Afterhyperpolarization in Cortical Neurons

Abstract

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_Cachannels, 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_Cachannels 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_mAHPis blocked by the SK_Cachannel blockers apamin and bicuculline, whereasI_sAHPis resistant to these agents but is inhibited by activation of muscarinic receptors. To test for a role for SK_Cachannels, we overexpressed K_Ca2.1 (SK1) and K_Ca2.2 (SK2), the predominant SK_Casubunits 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 ofI_mAHPbut had no detectable effect onI_sAHP. As an additional test, we examinedI_sAHPin a transgenic mouse expressing a truncated SK_Casubunit (SK3-1B) capable of acting as a dominant negative for the entire family of SK_Ca–IK_Cachannels. Expression of SK3-1B profoundly inhibitedI_mAHPbut again had no discernable effect onI_sAHP. These results are inconsistent with the proposal that SK_Cachannels mediateI_sAHPin pyramidal cells and indicate that a different potassium channel mediates this current.