Pharmacological modulation of SK3 channels

Morten Grunnet*, Thomas Jespersen, Kamilla Angelo, Christian Froekjaer Jensen, Dan A. Klaerke, Søren Peter Olesen, Bo Skaaning Jensen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

Abstract

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 and participate in afterhyperpolarization (AHP) and spike-frequency adaptation, pharmacological modulation of SK channels may be of significant clinical importance. Here we report the functional expression of SK3 in HEK293 and demonstrate a broad pharmacological profile for these channels. Brain slice studies commonly employ 4-aminopyridine (4-AP) to block voltage-dependent K+ channels or a methyl derivative of bicuculline, a blocker of gamma-aminobutyric acid (GABA)-gated Cl- channels, in order to investigate the role of various synapses in specialized neural networks. However, in this study both 4-AP and bicuculline are shown to inhibit SK3 channels (IC50 values of 512 μM and 6 μM, respectively) at concentrations lower than those used for brain slice recordings. Riluzole, a potent neuroprotective drug with anti-ischemic, anticonvulsant and sedative effects currently used in the treatment of amyotrophic lateral sclerosis, activates SK3 channels at concentrations of 3 μM and above. Amitriptyline, a tricyclic antidepressive widely used clinically, inhibits SK3 channels with an IC50 of 39.1±10 μM (n=6).

Original languageEnglish (US)
Pages (from-to)879-887
Number of pages9
JournalNeuropharmacology
Volume40
Issue number7
DOIs
StatePublished - Jun 18 2001

Keywords

  • 1-Ethylbenzimidiazolone
  • 4-Aminopyridine
  • Amitriptyline
  • Bicuculline
  • Ca-activated K channel
  • Riluzole

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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