Control of Electrical Activity in Central Neurons by Modulating the Gating of Small Conductance Ca2+-activated K+ Channels

• Published in: The Journal of biological chemistry Vol. 276; no. 13; pp. 9762 - 9769
• Main Authors: Pedarzani, Paola, Mosbacher, Johannes, Rivard, Andre, Cingolani, Lorenzo A., Oliver, Dominik, Stocker, Martin, Adelman, John P., Fakler, Bernd
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.03.2001; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Apamin - pharmacology; Benzimidazoles - pharmacology; Calcium - metabolism; Calcium Channel Agonists - pharmacology; Calmodulin - metabolism; Cells, Cultured; Central Nervous System - metabolism; Dose-Response Relationship, Drug; Electrophysiology; Hippocampus - cytology; Hippocampus - metabolism; Magnesium - pharmacology; Neurons - metabolism; Neurons - physiology; Oocytes - metabolism; Potassium Channels - metabolism; Potassium Channels - physiology; Potassium Channels, Calcium-Activated; Rats; Rats, Sprague-Dawley; Rats, Wistar; RNA, Messenger - metabolism; Small-Conductance Calcium-Activated Potassium Channels; Time Factors; Xenopus
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M010001200

In most central neurons, action potentials are followed by an afterhyperpolarization (AHP) that controls firing pattern and excitability. The medium and slow components of the AHP have been ascribed to the activation of small conductance Ca2+-activated potassium (SK) channels. Cloned SK channels are heteromeric complexes of SK α-subunits and calmodulin. The channels are activated by Ca2+ binding to calmodulin that induces conformational changes resulting in channel opening, and channel deactivation is the reverse process brought about by dissociation of Ca2+ from calmodulin. Here we show that SK channel gating is effectively modulated by 1-ethyl-2-benzimidazolinone (EBIO). Application of EBIO to cloned SK channels shifts the Ca2+ concentration-response relation into the lower nanomolar range and slows channel deactivation by almost 10-fold. In hippocampal CA1 neurons, EBIO increased both the medium and slow AHP, strongly reducing electrical activity. Moreover, EBIO suppressed the hyperexcitability induced by low Mg2+ in cultured cortical neurons. These results underscore the importance of SK channels for shaping the electrical response patterns of central neurons and suggest that modulating SK channel gating is a potent mechanism for controlling excitability in the central nervous system.