Activation of voltage-gated proton channels of rat microglia upon acute and prolonged cell acidosis

Abstract

Microglia participate in both neuroprotective and neuropathological functions. Voltage-gated proton (H⁺) channels, highly expressed in microglia, sense subtle pH disturbances and secrete a massive amount of H⁺. We hypothesize that the H⁺ channel plays a crucial role in H⁺-signaling in the CNS. Here the H⁺ channel activity in different types of cell acidosis was examined in rat microglia under actions of intrinsic pH buffers employing perforated whole-cell recordings. When washing pre-loaded NH₄Cl imposed acute cell acidosis, the H⁺ channel was activated immediately upon a drop in intracellular pH. The equilibrium potential for H⁺ (Er) shifted to more negative voltages, but the IV curve was identical. The activation was transient at voltages higher than the channel threshold, and sustained at voltages lower than the threshold, indicating that relief of the cell acidosis terminated the channel activation. When prolonged cell acidosis was induced by Na-lactate (pH 6.8), activation of the H⁺ channels was maintained accompanying by Er shift to negative voltages and enhancement of the IV curve. It is suggested that cell acidosis by washing NH₄Cl activates the H⁺ channel due to the inherent pH-dependency, but during lactoacidosis, pH-independent mechanisms also contribute to the activation. The H⁺ channel, as a real-time pH monitor, is a useful tool in investigating H⁺-signaling. [Jpn J Physiol 54 Suppl:S136 (2004)]