Small conductance Ca²⁺-activated K⁺ channels are regulated by Ca²⁺-calmodulin-dependent protein kinase II in murine colonic myocytes

1. Ca²⁺ regulates the activity of small conductance Ca²⁺-activated K⁺ (SK) channels via calmodulin-dependent binding. We investigated whether other forms of Ca²⁺-dependent regulation might control the open probability of SK channels. 2. Under whole-cell patch-clamp conditions, spontaneous openings of SK channels can be resolved as charybdotoxin-insensitive spontaneous transient outward currents (STOCs). The Ca²⁺-calmodulin-dependent (CaM) protein kinase II inhibitor KN-93 reduced the occurrence of charybdotoxin-insensitive STOCs. 3. The charybdotoxin-insensitive STOCs are related to spontaneous, local release of Ca²⁺. KN-93 did not affect spontaneous Ca²⁺-release events. 4. KN-93 and W-7, a calmodulin inhibitor, decreased the open probability of SK channels in on-cell patches but not in excised patches. 5. Application of autothiophosphorlated CaM kinase II to the cytoplasmic surface of excised patches increased the open probalibity of SK channels. Boiled CaM kinase II had no effect. 6. We conclude that CaM kinase II regulates SK channels in murine colonic myocytes. This mechanism provides a secondary means of regulation, increasing the impact of a given Ca²⁺ transient on SK channel open probability.