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Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, 124 Sherman Hall, University at Buffalo, The State University of New York, Buffalo, NY 14214-3005, USA
C-type inactivation is present in many voltage-gated potassium channels and is probably related to ‘slow’ inactivation in calcium and sodium channels. The mechanisms underlying C-type inactivation are unclear, but it is sensitive to mutations on both the extra- and intracellular sides of the channel. We used an N-terminal deleted channel with a valine to alanine point mutation at the intracellular side of S6 (fKv1.4[V561A]
N). This construct alters recovery from inactivation and inverts the relationship between C-type inactivation and [K+]o. We used this inverted relationship to examine C-type inactivation and coupling mechanisms between N- and C-type inactivation. The valine to alanine mutation reduces the channel's affinity for both quinidine and the N-terminal domain. However, binding of the N-terminal or quinidine restores normal recovery from inactivation. This suggests that coupling between N- and C-type inactivation is dominated by allosteric mechanisms. The permeation mechanism, driven by a reduction in permeant [K+]o following pore block (which would retard C-type inactivation), contributes minimally to coupling in these channels. We propose that the cytoplasmic half of S6 forms part of the N-terminal binding site, as previously predicted from X-ray crystallography studies in the distantly related KcsA channel. Binding of the N-terminal domain or a positively charged lipophilic compound such as quinidine interacts with the hydrophobic moieties on S6 in the bound state. This binding can orientate S6 into a conformation which resembles the normal C-type inactivated state. This is the probable mechanism by which drug or N-terminal binding increases the rate of C-type inactivation via an allosteric mechanism.
(Received 14 September 2003;
accepted after revision 24 October 2003;
first published online 7 November 2003)
Corresponding author R. L. Rasmusson: Department of Physiology and Biophysics, 124 Sherman Hall, State University of New York at Buffalo, Buffalo, NY 14214-3005, USA. Email: rr32{at}buffalo.edu
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