MODULATION OF C-TYPE INACTIVATION BY K+ AT THE POTASSIUM CHANNEL SELECTIVITY FILTER

With prolonged or repetitive activation, voltage-gated K+ channels und ergo a slow (C-type) inactivation mechanism, which decreases current f low through the channel. Previous observations suggest that C-type ina ctivation results from a localized constriction in the outer mouth of the channel pore and that the rate of inactivation is controlled by th e rate at which K+ leaves an unidentified binding site in the pore. We have functionally identified two K+ binding sites in the conduction p athway 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 selectivi ty filter mechanism for K+ over Na+. Another site, external to the hig h-affinity site, has a lower affinity for K+ and is not involved in ch annel selectivity Binding of K+ to the high-affinity binding site slow ed inactivation. Binding of cations to the external low-affinity site did not slow inactivation directly but could slow it indirectly, appar ently by trapping K+ at the high-affinity site. These data support a m odel whereby C-type inactivation involves a constriction at the select ivity filter, and the constriction cannot proceed when the selectivity filter is occupied by K+.