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Allosteric modulation of the mouse kir6.2 channel by intracellular H + and ATP
Author(s) -
Wu Jianping,
Cui Ningren,
Piao Hailan,
Wang Ying,
Xu Haoxing,
Mao Jinzhe,
Jiang Chun
Publication year - 2002
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2002.025247
Subject(s) - allosteric regulation , kir6.2 , intracellular ph , biophysics , intracellular , atp synthase gamma subunit , adenosine triphosphate , chemistry , chemiosmosis , protein subunit , sulfonylurea receptor , biochemistry , atp synthase , atp hydrolysis , enzyme , atpase , biology , gene
The ATP‐sensitive K + (K ATP ) channels 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 channel, 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 m m 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 m m 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 channel by ATP and H + are demonstrated. Such a regulation allows protons to activate directly the K ATP channels 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.