Specific Enhancement of SK Channel Activity Selectively Potentiates the Afterhyperpolarizing Current IAHP and Modulates the Firing Properties of Hippocampal Pyramidal Neurons

Abstract

SK channels are Ca2؉ -activated K ؉ channels that underlie after hyperpolarizing (AHP) currents and contribute to the shaping of the firing patterns and regulation of Ca 2؉ influx in a variety of neurons. The elucidation of SK channel function has recently benefited from the discovery of SK channel enhancers, the prototype of which is 1-EBIO. 1-EBIO exerts profound effects on neuronal excitability but displays a low potency and limited selectivity. This study reports the effects of DCEBIO, an intermediate conductance Ca 2؉ -activated K ؉ channel modulator, and the effects of the recently identified potent SK channel enhancer NS309 on recombinant SK2 channels, neuronal apamin-sensitive AHP currents, and the excitability of CA1 neurons. NS309 and DCEBIO increased the amplitude and duration of the apamin-sensitive afterhyperpolarizing current without affecting the slow afterhyperpolarizing current in contrast to 1-EBIO. The potentiation by DCEBIO and NS309 was reversed by SK channel blockers. In current clamp experiments, NS309 enhanced the medium afterhyperpolarization (but not the slow afterhyperpolarization sAHP) and profoundly affected excitability by facilitating spike frequency adaptation in a frequency-independent manner. The potent and specific effect of NS309 on the excitability of CA1 pyramidal neurons makes this compound an ideal tool to assess the role of SK channels as possible targets for the treatment of disorders linked to neuronal hyperexcitability.In hippocampal pyramidal neurons voltage-independent, Ca 2ϩ -activated K ϩ channels are responsible for the generation of two distinct afterhyperpolarizing currents, I AHP 5 and sI AHP (1-4). I AHP is characterized by a time constant of decay of ϳ100 ms and by its sensitivity to the bee venom toxin, apamin, and to the scorpion toxins, scyllatoxin and tamapin (5-7). sI AHP is characterized by a slower time course (in the range of seconds), by its lack of sensitivity to apamin or any other classical K ϩ channel blocker, and by its modulation by several neurotransmitters (1-3, 8). Based on their kinetic and pharmacological features and on the results obtained from genetically manipulated mice, SK channels mediate I AHP , whereas the molecular correlate for sI AHP is still unknown (2-4, 9, 10). In addition to the use of selective blockers, an important contribution to the elucidation of the physiological role of SK and IK channels has arisen from the use of a small organic compound that enhances channel activity, the benzimidazolinone 1-EBIO (11-15). 1-EBIO enhances the activity of SK channels in the presence of the physiological activator, intracellular Ca 2ϩ , by increasing the apparent sensitivity of SK channels to Ca 2ϩ (14). As a consequence, 1-EBIO increases the amplitude of SK-mediated AHP currents and their duration in a variety of neurons, leading to profound changes in neuronal activity and firing patterns (14, 16 -18). Although 1-EBIO has been a useful tool to elucidate the function of SK channels in their native context, it has some important li...

Ionic and neuromodulatory regulation of burst discharge controls frequency tuning

“…SK channels can regulate numerous aspects of neuronal dynamics including: spike frequency adaptation (Pedarzani et al, 2005), dendrosomatic coupling (Cai et al, 2004), as well as synaptic integration and potentiation (Faber et al, 2005;Ngo-Anh et al, 2005). The links between SK channel kinetics and behaviourally relevant neuronal computations have only recently begun to be examined for the SK2 subtype (Ellis et al, 2007b).…”

SK Channels Provide a Novel Mechanism for the Control of Frequency Tuning in Electrosensory Neurons

“…Small conductance calcium-activated potassium (SK) channels (Kohler et al, 1996) open in response to elevations in calcium and produce a medium afterhyperpolarization (mAHP). SK channels can regulate numerous aspects of neuronal dynamics including the following: spike frequency adaptation (Pedarzani et al, 2005), spike patterning (Wolfart et al, 2001;Cloues and Sather, 2003), synaptic excitability (Stackman et al, 2002;Kramar et al, 2004), dendrosomatic coupling (Womack and Khodakhah, 2003), and long-term potentiation (Behnisch and Reymann, 1998;Lancaster et al, 2001;Stackman et al, 2002;Faber et al, 2005;Ngo-Anh et al, 2005). The links between SK channel kinetics and behaviorally relevant neuronal computations have not, however, been rigorously explored.…”

α-Actinin2 cytoskeletal protein is required for the functional membrane localization of a Ca2+-activated K+channel (SK2 channel)

“…SK channels represent a highly unique family of K ϩ channels, in that they are directly gated by changes in intracellular Ca 2ϩ concentration and hence function to integrate changes in Ca 2ϩ concentration with changes in K ϩ conductance and membrane potentials. SK channels have been shown to mediate afterhyperpolarizations in neurons (9,12,13) and action potential repolarization in cardiac tissues (14,15). Previous studies have provided strong support that ion channels are components of macromolecular complexes containing the main pore-forming and auxiliary subunits interacting with scaffolding and regulatory proteins that are linked to the cytoskeleton (16).…”