Pharmacological modulation of SK3 channels

Small-conductance, calcium-activated K+ channels (SK channels) are voltage- insensitive channels that have been identified molecularly within the last few years. As SK channels play a fundamental role in most excitable cells a nd participate in afterhyperpolarization (AHP) and spike-frequency adaptati on, pharmacological modulation of SK channels may be of significant clinica l importance. Here we report the functional expression of SK3 in HEK293 and demonstrate a broad pharmacological profile for these channels. Brain slic e studies commonly employ 4-aminopyridine (4-AP) to block voltage-dependent K+ channels or a methyl derivative of bicuculline, a blocker of gamma-amin obutyric acid (GABA)-gated Cl- channels, in order to investigate the role o f various synapses in specialized neural networks. However, in this study b oth 4-AP and bicuculline are shown to inhibit SK3 channeld (IC50 values of 512 muM and 6 muM, respectively) at concentrations lower than those used fo r brain slice recordings. Riluzole, a potent neuroprotective drug with anti -ischemic, anticonvulsant and sedative effects currently used in the treatm ent of amyotrophic lateral sclerosis, activates SK3 channels at concentrati ons of 3 muM and above. Amitriptyline, a tricyclic antidepressive widely us ed clinically, inhibits SK3 channels with an IC50 of 39.1 +/- 110 CIM (n=6) . (C) 2001 Elsevier Science Ltd. All rights reserved.