PubMed · 679851
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K H Kimbel. 1978-09-08. [Biguanides].. https://pubmed.ncbi.nlm.nih.gov/679851/
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The biophysical and pharmacological properties of an oxygen-sensitive background K+ current in rat carotid body type-I cells were investigated and compared with those of recently cloned two pore domain K+ channels. Under symmetrical K+ conditions the oxygen-sensitive whole cell K+ current had a linear dependence on voltage indicating a lack of intrinsic voltage sensitivity. Single channel recordings identified a K+ channel, open at resting membrane potentials, that was inhibited by hypoxia. This channel had a single channel conductance of 14 pS, flickery kinetics and showed little voltage sensitivity except at extreme positive potentials. Oxygen-sensitive current was inhibited by 10 mM barium (57% inhibition), 200 microM zinc (53% inhibition), 200 microM bupivacaine (55% inhibition) and 1 mM quinidine (105 % inhibition). The general anaesthetic halothane (1.5%) increased the oxygen-sensitive K+ current (by 176%). Halothane (3 mM) also stimulated single channel activity in inside-out patches (by 240%). Chloroform had no effect on background K+ channel activity. Acidosis (pH 6.4) inhibited the oxygen-sensitive background K+ current (by 56%) and depolarised type-I cells. The pharmacological and biophysical properties of the background K+ channel are, therefore, analogous to those of the cloned channel TASK-1. Using in situ hybridisation TASK-1 mRNA was found to be expressed in type-I cells. We conclude that the oxygen- and acid-sensitive background K+ channel of carotid body type-I cells is likely to be an endogenous TASK-1-like channel.
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. 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 approximately 20 % and Kir4.1-Kir5.1 currents by approximately 60 %. 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. 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. 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. 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. 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 PCO2 and intracellular pH at physiological levels.
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