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Tedisamil blocks a calcium-dependent potassium channel in cultured motoneurons
J G McLarnon1, D Sawyer, M Michikawa
1Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada.
Abstract:
A calcium-dependent potassium channel K(Ca) has been isolated in mouse motoneurons. With physiological concentrations of potassium across inside-out patches, a 100 pS K(Ca) channel was activated when the bath solution of Ca2+ was in excess of 1 microM. Introduction of the drug tedisamil, a blocker of repolarizing potassium channels in cardiac cells, at concentrations in the range 0.2-10 microM, caused a dose-dependent decrease in the mean open times for K(Ca). The drug action was consistent with open channel block of K(Ca) with an onward (blocking) rate constant of 6 x 10(7) M-1 s-1. Tedisamil, at concentrations of 1 microM and 5 microM, also blocked the K(Ca) channel when applied to outside-out patches with a similar potency as found with internal application. A large conductance K(Ca) channel in hippocampal neurons is also blocked by a number of putative Class III antiarrhythmic drugs, including tedisamil; thus, these agents may have utility in the characterization of the properties of K(Ca) channels in various cells.
Insights
The drug tedisamil blocks calcium-dependent potassium channels (K(Ca)) in mouse motoneurons. This open channel block mechanism offers potential for characterizing K(Ca) channel properties in various cell types.
Area of Science:
- Neuroscience
- Ion Channel Physiology
- Pharmacology
Background:
- Calcium-dependent potassium channels (K(Ca)) play crucial roles in neuronal excitability.
- Understanding K(Ca) channel function is vital for neurological research and drug development.
Purpose of the Study:
- To investigate the effects of tedisamil on a specific K(Ca) channel in mouse motoneurons.
- To determine the mechanism and potency of tedisamil's interaction with K(Ca) channels.
Main Methods:
- Isolation of a 100 pS K(Ca) channel in mouse motoneurons using inside-out and outside-out patch-clamp techniques.
- Application of varying concentrations of calcium (Ca2+) and tedisamil to assess channel activation and block.
- Kinetic analysis to determine the rate constant of tedisamil's open channel block.
Main Results:
- The K(Ca) channel was activated by Ca2+ concentrations exceeding 1 microM.
- Tedisamil caused a dose-dependent reduction in K(Ca) channel mean open times.
- The drug exhibited open channel block kinetics with a rate constant of 6 x 10(7) M-1 s-1, consistent across internal and external application.
Conclusions:
- Tedisamil acts as an open channel blocker for mouse motoneuron K(Ca) channels.
- Tedisamil and similar Class III antiarrhythmic drugs may serve as valuable tools for studying K(Ca) channel properties in diverse cellular contexts.