Pflügers Archiv - European Journal of Physiology

, Volume 455, Issue 5, pp 829–838 | Cite as

Early and late activation of the voltage-gated proton channel during lactic acidosis through pH-dependent and -independent mechanisms

  • Hirokazu Morihata
  • Junko Kawawaki
  • Masako Okina
  • Hiromu Sakai
  • Takuya Notomi
  • Makoto Sawada
  • Miyuki KunoEmail author
Cell and Molecular Physiology


Voltage-gated proton (H+) channels play a pivotal role in compensating charge and pH imbalances during respiratory bursts in phagocytes. Lactic acidosis is a clinically important metabolic condition accompanying various tissue disorders in which the extracellular pH and the intracellular pH often change in parallel. In this study, we investigated the responses of the H+ channel in microglia to lactate-induced pH disturbances using the perforated-patch recordings. Na-lactate (pH 6.8) acidified the cells and activated the H+ channel within 5 min. This early activation was correlated with increases in the pH gradient across the plasma membrane (ΔpH) and was dose-dependent over a concentration range of 10–150 mM. At 10 mM, the change in ΔpH was only slight, but the H+ currents continued to increase over an hour after the cell acidosis was stabilized. Prolonged exposure to lactate (10–20 mM, >1 h) increased the amplitude by two to threefold. The late activation was not explained by increased ΔpH but by changes in the property of the channel per se. Pretreatment with staurosporine and chelerythrine, inhibitors for protein kinase C, prevented the late activation. These results suggest that the H+ channel could be activated greatly during long-lasting lactic acidosis through both ΔpH-dependent and -independent mechanisms.


Proton current Lactic acid Acidosis Protein kinase C pH 



We would like to thank Dr. Charles Edwards for critically reading the manuscript, Y. Moriura and K. Hiraoka for technical assistance, and Y. Yoshioka and M. Okamoto for secretary assistance. This work was supported by a Grant-in-Aid for Scientific Research from The Ministry of Education, Science, and Culture, Japan.


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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Hirokazu Morihata
    • 1
  • Junko Kawawaki
    • 2
  • Masako Okina
    • 1
  • Hiromu Sakai
    • 1
  • Takuya Notomi
    • 1
  • Makoto Sawada
    • 3
  • Miyuki Kuno
    • 1
    • 4
    Email author
  1. 1.Department of PhysiologyOsaka City University Graduate School of MedicineAbeno-kuJapan
  2. 2.Central LaboratoryOsaka City University Graduate School of MedicineOsakaJapan
  3. 3.Department of Brain Life Science, Research Institute of Environmental MedicineNagoya UniversityNagoyaJapan
  4. 4.Department of Molecular Physiology, Division of Intracellular MetabolismNational Institutes of Natural SciencesOkazakiJapan

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