Potentiation of a voltage-gated proton current in acidosis-induced swelling of rat microglia

Microglia are equipped with a strong proton (H+) extrusion pathway, a volta ge-gated H+ channel, probably to compensate for the large amount of H+ gene rated during phagocytosis; however, little is known about how this channel is regulated in pathological states. Because neural damage is often associa ted with intracellular and extracellular acidosis, we examined the regulato ry mechanisms of the H+ current of rat spinal microglia in acidic environme nts. More than 90% of round/amoeboid microglia expressed the H+ current, wh ich was characterized by slow activation kinetics, dependencies on both int racellular and extracellular pH, and blockage by Zn2+. Extracellular lactoa cidosis, pH 6.8, induced intracellular acidification and cell swelling. Cel l swelling was also induced by intracellular dialysis with acidic pipette s olutions, pH 5.5-6.8, at normal extracellular pH 7.3 in the presence of Na. The H+ currents were increased in association with cell swelling as shown by shifts of the half-activation voltage to more negative potentials and b y acceleration of the activation kinetics. The acidosis-induced cell swelli ng and the accompanying potentiation of the H+ current required nonhydrolyt ic actions of intracellular ATP and were inhibited by agents affecting acti n filaments (phalloidin and cytochalasin D). The H+ current was also potent iated by swelling caused by hypotonic stress. These findings suggest that t he H+ channel of microglia can be potentiated via cell swelling induced by intracellular acidification. This potentiation might operate as a negative feedback mechanism to protect microglia from cytotoxic acidification and he nce acidosis-induced swelling in pathological states of the CNS.