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Biophys. J. BioFAST: First Published January 19, 2007. doi:10.1529/biophysj.106.101287
© 2007 by the Biophysical Society.

A more recent version of this article appeared on April 15, 2007.
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Henrik Sindal Jensen
Morten Grunnet
Søren-Peter Olesen
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CHANNELS, RECEPTORS, AND ELECTRICAL SIGNALING

Inactivation as a new regulatory mechanism for neuronal Kv7 channels

Henrik Sindal Jensen 1*, Morten Grunnet 2 and Søren-Peter Olesen 3

1 H. Lundbeck A/S
2 NeuroSearch A/S
3 The Panum Institute at University of Copenhagen

* To whom correspondence should be addressed. E-mail: hsin{at}lundbeck.com.

Submitted on November 16, 2006
Revised on December 27, 2006
Accepted on 4 January 2007


  Abstract
Voltage-gated K+ channels of the Kv7 (KCNQ) family have important physiological functions in both excitable and non-excitable tissue. The family encompasses five genes encoding the channel subunits Kv7.1-5. Kv7.1 is found in epithelial and cardiac tissue. Kv7.2-5 channels are predominantly neuronal channels and are important for controlling excitability. Kv7.1 channels have been considered the only Kv7 channel to undergo inactivation upon depolarization. However, here we demonstrate that inactivation is also an intrinsic property of Kv7.4 and Kv7.5 channels, which inactivate to a larger extent than Kv7.1 channels at all potentials. We demonstrate that at least 30 % of these channels are inactivated at physiologically relevant potentials. The onset of inactivation is voltage-dependent and occurs in the order of seconds. Both time- and voltage-dependent recovery from inactivation was investigated for Kv7.4 channels. A time-constant of 1.47 ± 0.21 s and a voltage-constant of 54.9 ± 3.4 mV were determined. It was further demonstrated that heteromeric Kv7.3/Kv7.4 channels had inactivation properties different from homomeric Kv7.4 channels. Finally, the Kv7 channel activator BMS-204352 was in contrast to retigabine found to abolish inactivation of Kv7.4. In conclusion, the present paper demonstrates that inactivation is a key regulatory mechanism of Kv7.4 and Kv7.5 channels.

Key Words: BMS-204352, KCNQ, Kv7, inactivation, potassium channel, retigabine




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Copyright © 2007 by the Biophysical Society.