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 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 microM and 6 microM, 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 microM and above. Amitriptyline, a tricyclic antidepressive widely used clinically, inhibits SK3 channels with an IC50 of 39.1 +/- 10 microM (n=6).
Grunnet
M
M
Division of Cellular and Molecular Physiology, Department of Medical Physiology, The Panum Institute, University of Copenhagen, 3 Blegdamsvej, DK-2200 N, Copenhagen, Denmark. mgrunnet@mfi.ku.dk
Jespersen
T
T
Angelo
K
K
Frøkjaer-Jensen
C
C
Klaerke
D A
DA
Olesen
S P
SP
Jensen
B S
BS
D015761:4-Aminopyridine / Q000494:pharmacology; D000639:Amitriptyline / Q000494:pharmacology*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001030:Apamin / Q000494:pharmacology; D001640:Bicuculline / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated; D051381:Rats; D019782:Riluzole / Q000494:pharmacology*; D051640:Small-Conductance Calcium-Activated Potassium Channels
D000929:Antidepressive Agents, Tricyclic; C496901:Kcnn3 protein, rat; D018696:Neuroprotective Agents; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D051640:Small-Conductance Calcium-Activated Potassium Channels; D000639:Amitriptyline; D001030:Apamin; C036615:bicuculline methobromide; D019782:Riluzole; D015761:4-Aminopyridine; D001640:Bicuculline