The biophysical properties of small conductance Ca 2؉ -activated K ؉ (SK) channels are well suited to underlie afterhyperpolarizations (AHPs) shaping the firing patterns of a conspicuous number of central and peripheral neurons. We have identified a new scorpion toxin (tamapin) that binds to SK channels with high affinity and inhibits SK channel-mediated currents in pyramidal neurons of the hippocampus as well as in cell lines expressing distinct SK channel subunits. This toxin distinguished between the SK channels underlying the apamin-sensitive I AHP and the Ca 2؉ -activated K ؉ channels mediating the slow I AHP (sI AHP ) in hippocampal neurons. Compared with related scorpion toxins, tamapin displayed a unique, remarkable selectivity for SK2 versus SK1 (ϳ1750-fold) and SK3 (ϳ70-fold) channels and is the most potent SK2 channel blocker characterized so far (IC 50 for SK2 channels ‫؍‬ 24 pM). Tamapin will facilitate the characterization of the subunit composition of native SK channels and help determine their involvement in electrical and biochemical signaling.

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Taicatoxin, isolated from the venom of the Australian taipan snake Oxyuranus scutellatus, has been previously regarded as a specific blocker of high threshold Ca 2؉ channels in heart. Here we show that taicatoxin (in contrast to a range of other Ca 2؉ channel blockers) interacts with apamin-sensitive, small conductance, Ca 2؉ -activated potassium channels on both chromaffin cells and in the brain. Taicatoxin displays high affinity recognition of 125 I-apamin acceptor-binding sites, present on rat synaptosomal membranes (K i ‫؍‬ 1.45 ؎ 0.22 nM) and also specifically blocks affinity-labeling of a 33-kDa 125 I-apamin-binding polypeptide on rat brain membranes. Taicatoxin (50 nM) completely blocks apaminsensitive after-hyperpolarizing slow tail K ؉ currents generated in rat chromaffin cells (mean block 97 ؎ 3%, n ‫؍‬ 12) while only partially reducing total voltage-dependent Ca 2؉ currents (mean block 12 ؎ 4%, n ‫؍‬ 6). In view of these findings, the use of taicatoxin as a specific ligand for Ca 2؉ channels should now be reconsidered.