Membrane Biology
Uncoupling Charge Movement from Channel Opening in Voltage-gated Potassium Channels by Ruthenium Complexes*

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The Kv2.1 channel generates a delayed-rectifier current in neurons and is responsible for modulation of neuronal spike frequency and membrane repolarization in pancreatic β-cells and cardiomyocytes. As with other tetrameric voltage-activated K+-channels, it has been proposed that each of the four Kv2.1 voltage-sensing domains activates independently upon depolarization, leading to a final concerted transition that causes channel opening. The mechanism by which voltage-sensor activation is coupled to the gating of the pore is still not understood. Here we show that the carbon-monoxide releasing molecule 2 (CORM-2) is an allosteric inhibitor of the Kv2.1 channel and that its inhibitory properties derive from the CORM-2 ability to largely reduce the voltage dependence of the opening transition, uncoupling voltage-sensor activation from the concerted opening transition. We additionally demonstrate that CORM-2 modulates Shaker K+-channels in a similar manner. Our data suggest that the mechanism of inhibition by CORM-2 may be common to voltage-activated channels and that this compound should be a useful tool for understanding the mechanisms of electromechanical coupling.

Ion Channels
Membrane Biophysics
Neurobiology
Neuroscience
Potassium Channels
Channel Gating
Electromechanical Coupling
Voltage Dependence

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*

This study was supported by Consejo Nacional de Ciencia y Tecnologia Grant 48990, Dirección General de Asuntos del Personal Académico-PAPIIT Grant IN209209, and Instituto de Ciencia y Tecnología del Distrito Federal Grant PIFUTP09-262 (to L. D. I.).

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–4, Scheme 1, and Table 1.

1

This study was performed in partial fulfillment of the requirement for the doctoral degree in Biomedical Sciences at Universidad Nacional Autónoma de México.