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Biophysical Journal 86:2145-2155 (2004)
© 2004 The Biophysical Society

Potassium-Dependent Slow Inactivation of Kir1.1 (ROMK) Channels

H. Sackin *, L.G. Palmer {dagger} and M. Krambis *

* Department of Physiology and Biophysics, The Chicago Medical School, North Chicago, Illinois; and {dagger} Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York

Correspondence: Address reprint requests to Dr. Henry Sackin, Dept. of Physiology and Biophysics, The Chicago Medical School, 3333 Green Bay Rd., North Chicago, IL 60064. Tel.: 847-578-8329; Fax: 847-578-3265; E-mail: sackinh{at}finchcms.edu.

The ROMK (Kir1.1) family of epithelial K channels can be inactivated by a combination of low internal pH and low external K, such that alkalization does not reopen the channels unless external K is elevated. Previous work suggested that this inactivation results from an allosteric interaction between an inner pH gate and an outer K sensor, and could be described by a simple three-state kinetic model. In the present study, we report that a sustained depolarization slowly inactivated (half-time = 10–15 min) ROMK channels that had been engineered for increased affinity to internal polyamines. Furthermore, this inactivation occurred at external [K] <=1 mM in ROMK mutants whose inner pH gate was constitutively open (ROMK2-K61M mutation). Both pH and voltage inactivation depended on external K in a manner reminiscent of C-type inactivation, but having a much slower time course. Replacement of ROMK extracellular loop residues by Kir2.1 homologous residues attenuated or abolished this inactivation. These results are consistent with the hypothesis that there are (at least) two separate closure processes in these channels: an inner pH-regulated gate, and an outer (inactivation) gate, where the latter is modulated by both voltage and external [K].




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