Apamin Boosting of Synaptic Potentials in Ca(V)2.3 R-Type Ca(2+) Channel Null Mice

SK2- and K(V)4.2-containing K(+) channels modulate evoked synaptic potentials in CA1 pyramidal neurons. Each is coupled to a distinct Ca(2+) source that provides Ca(2+)-dependent feedback regulation to limit AMPA receptor (AMPAR)- and NMDA receptor (NMDAR)-mediated postsynaptic depolarization. SK2-containing channels are activated by Ca(2+) entry through NMDARs, whereas K(V)4.2-containing channel availability is increased by Ca(2+) entry through SNX-482 (SNX) sensitive Ca(V)2.3 R-type Ca(2+) channels. Recent studies have challenged the functional coupling between NMDARs and SK2-containing channels, suggesting that synaptic SK2-containing channels are instead activated by Ca(2+) entry through R-type Ca(2+) channels. Furthermore, SNX has been implicated to have off target affects, which would challenge the proposed coupling between R-type Ca(2+) channels and K(V)4.2-containing K(+) channels. To reconcile these conflicting results, we evaluated the effect of SK channel blocker apamin and R-type Ca(2+) channel blocker SNX on evoked excitatory postsynaptic potentials (EPSPs) in CA1 pyramidal neurons from Ca(V)2.3 null mice. The results show that in the absence of Ca(V)2.3 channels, apamin application still boosted EPSPs. The boosting effect of Ca(V)2.3 channel blockers on EPSPs observed in neurons from wild type mice was not observed in neurons from Ca(V)2.3 null mice. These data are consistent with a model in which SK2-containing channels are functionally coupled to NMDARs and K(V)4.2-containing channels to Ca(V)2.3 channels to provide negative feedback regulation of EPSPs in the spines of CA1 pyramidal neurons.