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Permeant Cations and Blockers Modulate pH Gating of ROMK Channels

Department of Physiology and Biophysics, The Chicago Medical School, North Chicago, Illinois 60064; and ^* Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York 10021

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}mis.finchcms.edu.

External potassium (K) activates the inward rectifier ROMK (K_ir1.1) by altering the pH gating of the channel. The present study examines this link between external K and internal pH sensitivity using both the two-electrode voltage clamp and the perfused, cut-open Xenopus oocyte preparation. Elevating extracellular K from 1 mM to 10 mM to 100 mM activated ROMK channels by shifting their apparent pK_a from 7.2 ± 0.1 (n = 6) in 1 mM K, to 6.9 ± 0.02 (n = 5) in 10 mM K, and to 6.6 ± 0.03 (n = 5) in 100 mM K. At any given internal pH, the number of active ROMK channels is a saturating function of external [K]. Extracellular Cs (which blocks almost all inward K current) also stimulated outward ROMK conductance (at constant 1 mM external K) by shifting the apparent pK_a of ROMK from 7.2 ± 0.1 (n = 6) in 1 mM K to 6.8 ± 0.01 (n = 4) in 1 mM K + 104 mM Cs. Surprisingly, the binding and washout of the specific blocker, Tertiapin-Q, also activated ROMK in 1 mM K and caused a comparable shift in apparent pK_a. These results are interpreted in terms of both a three-state kinetic model and a two-gate structural model that is based on results with KcsA in which the selectivity filter can assume either a high or low K conformation. In this context, external K, Cs, and Tertiapin-Q activate ROMK by destabilizing the low-K (collapsed) configuration of the selectivity filter.

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