Received May 24, 2002
Accepted after revision June 14, 2002

Allosteric modulation of the mouse KIR6.2 channel by intracellular H⁺ and ATP

¹ Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30302- 4010, USA
² Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, Georgia 30302- 4010, USA

^* To whom correspondence should be addressed.

The ATP-sensitive K⁺ channels (K_ATP) are regulated by intracellular H⁺ in addition to ATP, ADP, and phospholipids. Here we show evidence for the interaction of H⁺ with ATP in regulating a cloned K_ATP, i.e. Kir6.2 expressed with and without the SUR1 subunit. Channel sensitivity to ATP decreases at acidic pH, while the pH sensitivity also drops in the presence of ATP. These effects are more evident in the presence of the SUR1 subunit. In the Kir6.2 + SUR1, the pH sensitivity is reduced by about 0.4 pH units with 100 µM ATP and 0.6 pH units with 1 mM ATP, while a decrease in pH from 7.4 to 6.8 lowers the ATP sensitivity by about fourfold. The Kir6.2 + SUR1 currents are strongly activated at pH 5.9-6.5 even in the presence of 1 mM ATP. The modulations appear to take place at His175 and Lys185 that are involved in proton and ATP sensing, respectively. Mutation of His175 completely eliminates the pH effect on the ATP sensitivity. Similarly, the K185E mutant-channel loses the ATP-dependent modulation of the pH sensitivity. Thus, allosteric modulations of the cloned K_ATP by ATP and H⁺ are demonstrated. Such a regulation allows protons to activate directly the K_ATP and release channel inhibition by intracellular ATP; the pH effect is further enhanced with a decrease in ATP concentration as seen in several pathophysiological conditions.

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