Pharmacological activation and inhibition of Slack (Slo2.2) channels.
The Slack (Sequence like a calcium-activated K channel) (Slo2.2) gene is abundantly expressed in the mammalian brain and encodes a sodium-activated K+ (KNa) channel. Although the specific roles of Slack channel subunits in neurons remain to be identified, they may play a role in the adaptation of firing rate and in protection against ischemic injury. In the present study, we have generated a stable cell line expressing the Slack channel, and have analyzed the pharmacological properties of these channels in these cells and in Xenopus oocytes. Two known blockers of KNa channels, bepridil and quinidine, inhibited Slack currents in a concentration-dependent manner and decreased channel activity in excised membrane patches. The inhibition by bepridil was potent, with an IC50 of 1.0 microM for inhibition of Slack currents in HEK cells. In contrast, bithionol was found to be a robust activator of Slack currents. When applied to the extracellular face of excised patches, bithionol rapidly induced a reversible increase in channel opening, suggesting that it acts on Slack channels relatively directly. These data establish an important early characterization of agents that modulate Slack channels, a process essential for the experimental manipulation of Slack currents in neurons.
Yang
Bo
B
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Gribkoff
Valentin K
VK
Pan
Jennifer
J
Damagnez
Veronique
V
Dworetzky
Steven I
SI
Boissard
Christopher G
CG
Bhattacharjee
Arin
A
Yan
Yangyang
Y
Sigworth
Fred J
FJ
Kaczmarek
Leonard K
LK
D000818:Animals; D000891:Anti-Infective Agents, Local / Q000494:pharmacology; D015764:Bepridil / Q000494:pharmacology; D001735:Bithionol / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D024681:Potassium Channels, Calcium-Activated / Q000235:genetics / Q000502:physiology*; D011802:Quinidine / Q000494:pharmacology; D014162:Transfection; D014981:Xenopus
D000891:Anti-Infective Agents, Local; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D024681:Potassium Channels, Calcium-Activated; D015764:Bepridil; D001735:Bithionol; D011802:Quinidine