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Modulation of Kir4.1 and Kir5.1 by hypercapnia and intracellular acidosis

Haoxing Xu, Ningren Cui, Zhenjiang Yang, Zhiqiang Qu and Chun Jiang

1. CO₂ chemoreception may be mediated by the modulation of certain ion channels in neurons. Kir4.1 and Kir5.1, two members of the inward rectifier K⁺ channel family, are expressed in several brain regions including the brainstem. To test the hypothesis that Kir4.1 and Kir5.1 are modulated by CO₂ and pH, we carried out experiments by expressing Kir4.1 and coexpressing Kir4.1 with Kir5.1 (Kir4.1-Kir5.1) in Xenopus oocytes. K⁺ currents were then studied using two-electrode voltage clamp and excised patches.

2. Exposure of the oocytes to CO₂ (5, 10 and 15 %) produced a concentration-dependent inhibition of the whole-cell K⁺ currents. This inhibition was fast and reversible. Exposure to 15 % CO₂ suppressed Kir4.1 currents by 20 % and Kir4.1-Kir5.1 currents by 60 %.

3. The effect of CO₂ was likely to be mediated by intracellular acidification, because selective intracellular, but not extracellular, acidification to the measured hypercapnic pH levels lowered the currents as effectively as hypercapnia.

4. In excised inside-out patches, exposure of the cytosolic side of membranes to solutions with various pH levels brought about a dose-dependent inhibition of the macroscopic K⁺ currents. The pK value (-log of dissociation constant) for the inhibition was 6·03 in the Kir4.1 channels, while it was 7·45 in Kir4.1-Kir5.1 channels, an increase in pH sensitivity of 1·4 pH units.

5. Hypercapnia without changing pH did not inhibit the Kir4.1 and Kir4.1-Kir5.1 currents, suggesting that these channels are inhibited by protons rather than molecular CO₂.

6. A lysine residue in the N terminus of Kir4.1 is critical. Mutation of this lysine at position 67 to methionine (K67M) completely eliminated the CO₂ sensitivity of both the homomeric Kir4.1 and heteromeric Kir4.1-Kir5.1.

7. These results therefore indicate that the Kir4.1 channel is inhibited during hypercapnia by a decrease in intracellular pH, and the coexpression of Kir4.1 with Kir5.1 greatly enhances channel sensitivity to CO₂/pH and may enable cells to detect both increases and decreases in P_CO2 and intracellular pH at physiological levels.

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