Functional roles of SK2 channels in area CA1 of the hippocampus

Ca+-activated small-conductance K+ (SK) channels play a fundamentally important role in all excitable cells. They are potassium selective, voltage-insensitive and are activated by increases in the levels of intracellular Ca+ such as occur during an action potential (Zhang et al., 1995; Kohler et al., 1996; Sah et al., 1991; Lorenzen et al., 1992). As the action potential decays, the membrane potential is repolarized, and internal Ca+ levels rise, evoking a biphasic afterhyperpolarization. The initial faster phase is thought to be due to the activation of large-conductance voltageand Ca+-activated K+ (BK) channels, while the slower phase is thought to be due to the activation of SK channels, which are gated solely by intracellular Ca+ ions (Storm, 1990; Sah, 2002). While it is clear that SK channels mediate an apamin-sensitive current in CAl pyramidal neurons, there has been controversy as to whether or not SK channels contribute to the afterhyperpolarization (Bond et al., 2004; Gu et al., 2005). Increases in the intracellular Ca+ concentration activate SK channels, leading to hyperpolarization of the membrane potential, which in turn reduces the Ca+ inflow into the cell. This feedback mechanism is ideally suited to regulate the spatiotemporal occurrence of Ca+ transients: as SK channels activate, they extrude potassium from the cell, moving the membrane to more negative potentials. The recovery of the Ca+ signal following an action potential is slow, permitting SK channels to generate a long-lasting hyperpolarization with a time course that reflects the decay of intracellular Ca+. Thus, activation of SK channels causes membrane hyperpolarization, which inhibits cell firing.