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Modulation of C-Type Inactivation by K⁺ at the Potassium Channel Selectivity Filter

Laszlo Kiss and Stephen J. Korn^,  

Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut 06269 USA

Address reprint requests to Dr. Stephen Korn, Department of Physiology and Neurobiology, Box U-156, University of Connecticut, 3107 Horsebarn Hill Road, Storrs, CT 06269. Tel.: 860-486-4554; Fax: 860-486-3303.

Abstract

With prolonged or repetitive activation, voltage-gated K⁺ channels undergo a slow (C-type) inactivation mechanism, which decreases current flow through the channel. Previous observations suggest that C-type inactivation results from a localized constriction in the outer mouth of the channel pore and that the rate of inactivation is controlled by the rate at which K⁺ leaves an unidentified binding site in the pore. We have functionally identified two K⁺ binding sites in the conduction pathway of a chimeric K⁺ channel that conducts Na⁺ in the absence of K⁺. One site has a high affinity for K⁺ and contributes to the selectivity filter mechanism for K⁺ over Na⁺. Another site, external to the high-affinity site, has a lower affinity for K⁺ and is not involved in channel selectivity. Binding of K⁺ to the high-affinity binding site slowed inactivation. Binding of cations to the external low-affinity site did not slow inactivation directly but could slow it indirectly, apparently by trapping K⁺ at the high-affinity site. These data support a model whereby C-type inactivation involves a constriction at the selectivity filter, and the constriction cannot proceed when the selectivity filter is occupied by K⁺.