Abstract Small-conductance calcium-activated K+ channels (SK channels) regulate the excitability of neurons and their responsiveness to synaptic input patterns. his laboratory to the University of Chicago. He performed his PhD work in the laboratory of Wolf Singer at TMP 269 cost the Max-Planck-Institute for Brain Research in Frankfurt, and trained as a postdoc in the laboratory of David Linden at Johns Hopkins University. From 2000 to 2008 he was leading a research group at the Erasmus University Medical Center in Rotterdam. His work focuses on synaptic and non-synaptic mechanisms of information storage and learning in cerebellar circuits. Introduction Small-conductance calcium-activated K+ channels (SK channels) are strictly voltage-independent K+ channels that are exclusively activated by intracellular calcium ions (K?hler 1996; Xia 1998). SK channels are tetrameric assemblies of four -subunits that form the channel pore and bind to the calcium sensor calmodulin. Calcium binding to calmodulin triggers conformational changes in the channel complex and subsequent channel gating (Xia 1998; Lujan 2009). Three types of SK channel subunits, SK1C3, have been described in the CNS, which show very similar calcium sensitivities (EC50 = 0.3C0.5 m) and rely on a calmodulin-dependent gating mechanism (K?hler 1996; Xia 1998). SK channels open K+ conductances in response to calcium transients that result from membrane depolarization, and thus contribute to the TMP 269 cost repolarization of neurons. This effect is most evident in the participation of SK conductances in the afterhyperpolarization (AHP) following bursts of action potentials (Sah, 1996; Stocker 1999; Pedarzani 2001; Edgerton & Reinhart, 2003). SK channels thus provide a negative feedback loop that regulates the excitability of TMP 269 cost neurons. SK channel gating is controlled by complex protein kinase and phosphatase interactions. Each channel subunit constitutively binds casein kinase 2 (CK2) and protein phosphatase 2A (PP2A). CK2 is a constitutively active kinase that phosphorylates calmodulin bound to SK subunits and reduces the calcium sensitivity of SK channels (Bildl 2004). PP2A binds to SK channels as well and provides a phosphorylation switch with CK2 (Allen 2007). While the molecular composition of the SK channel multiprotein complex has been studied in detail (Lujan 2009), it remains to be determined under what physiological conditions the calcium sensitivity of SK channels is modified BAIAP2 by CK2 and PP2A. Voltage-clamp recordings reveal distinct kinetic phases of the AHP current: a fast component (1999), and a slow component (1999). Knock-out studies show that SK2 channels mediate 2004). The contribution of SK channels to an AHP current with a duration of tens to hundreds of milliseconds corresponds well with the observation that SK channel blockade by apamin enhances the spike frequency of neurons within bursts of action potentials, and the number of action potentials evoked by current injection (Stocker 1999). SK TMP 269 cost conductances also mediate the repolarization of dendritic plateau potentials (Cai 2004) and regulate calcium transients in dendritic spines (Ngo-Anh 2005; Belmeguenai 2010), which shows that SK channels control dendritic integration properties. Together, these data suggest that the main function of SK channels is to put a brake on neuronal firing and dendritic excitability in response to even moderate rises in the cytosolic calcium concentration. This review focuses on SK channel function in cerebellar Purkinje cells. These cells differ from many other types of neurons, including hippocampal and neocortical pyramidal cells, in their spike firing properties as well as in synaptic and non-synaptic plasticity mechanisms used for information storage (Hansel 2001; J?rntell & Hansel, 2006). We will discuss how SK channel modulation specifically regulates these processes in Purkinje cells. SK channel expression in cerebellar Purkinje cells Of the three types of SK channel subunits, only SK2 channels are expressed in rat Purkinje cells (Cingolani 2002). Therefore, apamin sensitivity in Purkinje cells can be exclusively assigned to SK2 channels (see Grunnet 2001). It has been reported that in rat Purkinje cells the level of SK2 channel expression significantly decreases during the first 3 weeks after birth, at both the mRNA and protein levels, with weak expression remaining in scattered Purkinje cells at P60 (Cingolani 2002). This decrease in SK2 channel expression was reflected in the observation that in adult Purkinje cells apamin failed.