Pharmacological modulation of SK3 channels

• Published in: Neuropharmacology 2001-06, Vol.40 (7), p.879-887
• Main Authors: Grunnet, Morten, Jespersen, Thomas, Angelo, Kamilla, Frøkjær-Jensen, Christian, Klaerke, Dan A, Olesen, Søren-Peter, Jensen, Bo Skaaning
• Format: Article
• Language: English
• Subjects: 1-Ethylbenzimidiazolone; 4-Aminopyridine; 4-Aminopyridine - pharmacology; Amitriptyline; Amitriptyline - pharmacology; Animals; Antidepressive Agents, Tricyclic - pharmacology; Apamin - pharmacology; Bicuculline; Bicuculline - analogs & derivatives; Bicuculline - pharmacology; Biological and medical sciences; Ca 2+-activated K + channel; Cell Line; Cell membranes. Ionic channels. Membrane pores; Cell structures and functions; Fundamental and applied biological sciences. Psychology; Humans; Medical sciences; Molecular and cellular biology; Neuropharmacology; Neuroprotective agent; Neuroprotective Agents - pharmacology; Pharmacology. Drug treatments; Potassium Channels - drug effects; Potassium Channels - metabolism; Potassium Channels, Calcium-Activated; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Rats; Riluzole; Riluzole - pharmacology; Small-Conductance Calcium-Activated Potassium Channels
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/S0028-3908(01)00028-4

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 (IC 50 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 IC 50 of 39.1±10 μM ( n=6).