Proton signaling mediated by voltagegated proton channels

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We have investigated how the voltage-gated proton (H^+) channels regulate H^+ signaling in osteoclasts, microglia and bone-marrow-derived mast cells (BMMC). The Q_<10> value was > 2.0 for conductance and 3 -6 for gating parameters. These high Q_<10> values were preserved well in both microglia and BMMC, which differed in the expression rate of the channel, implying that the high temperature dependence resides in the channel itself. The Q_<10> value for the conductance was, however, often decreased at high temperature or in swollen cells, thus, indicating that the activation status of the H^+ channel is heterogeneous. To clarify actions of the H^+ channel in intact cells, the channel activity in response to various types of cell acidosis was examined in the perforated-whole cell recordings under intrinsic pH buffers. In osteoclasts, an activator for protein kinase C, PMA, induced cell acidosis and activation of the H^+ channel. The reversal potential was served as a real-time monitor for changes in cellular pH in clamped cells. In microglia, the H^+ channel was activated accompanying either acute or prolonged cell acidosis. The channel activation terminated upon removal of the acidosis due to the H^+ extrusion. A part of the activation was, however, modified by ΔpH-independent processes. In addition, sometimes increases in intracellular Ca^<2+> or flux of CL^-, a counter ion for H^+, were associated with the acidosis. Thus H^+ signaling is intimately related to synergistic actions of other ion signals. This study has provided evidences that the H^+ can maintain cellular pH homeostasis by sensing minor changes in pH disturbances and, simultaneously, would trigger H^+ to the surrounding cells.