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External K Activation of Kir1.1 Depends on the pH Gate

Henry Sackin ^*, Mikheil Nanazashvili ^*, Hui Li ^*, Lawrence G. Palmer  and D. Eric Walters 

^* Department of Physiology and Biophysics, Department of Biochemistry and Molecular Biology, The Chicago Medical School, Illinois; and Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York

Correspondence: Address reprint requests and inquiries to Henry Sackin, Tel.: 847-578-8329; E-mail: henry.sackin{at}rosalindfranklin.edu.

The inward rectifier Kir1.1 (ROMK) family is gated by both internal pH and external K, where the putative pH gate is formed by the convergence of leucine side chains, near the inner helical bundle crossing at L160-Kir1.1. However, it is unclear whether K activation is mediated at the pH gate or by another gate in the permeation path. In this study, we used the whole-cell conductance increase during rapid K elevation as a measure of K activation, assuming that activation is inherently slower than changes in channel conduction. Results indicate that structural disruption of the Kir1.1 bundle-crossing pH gate prevents both inactivation by low external K and reactivation by high external K.