Inhibition of store-operated Ca2+ influx by acidic extracellular pH in cultured human microglia

The effects of extracellular acidification on Ca2+-dependent signaling pathways in human microglia were investigated using Ca2+-sensitive fluorescence microscopy. Adenosine triphosphate (ATP) was used to elicit Ca2+ responses primarily dependent on the depletion of intracellular endoplasmic reticulum (ER) stores, while platelet-activating factor (PAF) was used to elicit responses primarily dependent on store-operated channel (SOC) influx of Ca2+. The duration of transient responses induced by ATP was not significantly different in standard physiological pH 7.4 (mean duration 30.2 +/- 2.5 s) or acidified pH 6.2 (mean duration 31.7 +/- 2.8 s) extracellular solutions. However, the time course of the PAF response at pH 7.4 was significantly reduced by 87% with external pH at 6.2. These results suggest that acidification of extracellular solutions inhibits SOC entry of Ca2+ with little or no effect on depletion of ER stores. Changes of extracellular pH over the range from 8.6 to 6.2 during the development of a sustained SOC influx induced by PAF resulted in instantaneous modulation of SOC amplitude indicating a rapidly reversible effect of pH on this Ca2+ pathway. Whole-cell patch clamp recordings showed external acidification blocked depolarization-activated outward K+ current indicating cellular depolarization may be involved in the acid pH inhibition. Since SOC mediated influx of Ca2+ is strongly modulated by membrane potential, the electrophysiological data suggest that acidification may act to inhibit SOC by cellular depolarization. These results suggest that acidification observed during cerebral ischemia may alter microglial responses and functions. (C) 2001 Wiley-Liss, Inc.