CO(2) inhibits specific inward rectifier K(+) channels by decreases in intra- and extracellular pH

Hypercapnia has been shown to affect cellular excitability by modulating K+ channels. To understand the mechanisms for this modulation, four cloned K+ channels were studied by expressing them in Xenopus oocytes. Exposures of the oocytes to CO2 for 4–6 min produced reversible and concentration-dependent inhibitions of Kir1.1 and Kir2.3 currents, but had no effect on Kir2.1 and Kir6.1 currents. Intra- and extracellular pH (pHi, pHo) dropped during CO2 exposures. The inhibition of Kir2.3 currents was mediated by reductions in both intra- and extracellular pH, whereas the suppression of Kir1.1 resulted from intracellular acidification. In cell-free excised inside-out patches with cytosolic-soluble factors washed out, a decrease in pHi produced a fast and reversible inhibition of macroscopic Kir2.3 currents. The degree of this inhibition was similar to that produced by hypercapnia when compared at the same pHi level. Exposure of cytosolic surface of patch membranes to a perfusate bubbled with 15% CO2 without changing pH failed to inhibit the Kir2.3 currents. These results therefore indicate that (1) hypercapnia inhibits specific K+ channels, (2) these inhibitions are caused by intra- and extracellular protons rather than molecular CO2, and (3) these effects are independent of cytosol-soluble factors. J. Cell. Physiol. 183:53–64, 2000. © 2000 Wiley-Liss, Inc.