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

The effects of extracellular acidification on Ca2+-dependent signaling path ways 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 reticulu m (ER) stores, while platelet-activating factor (PAF) was used to elicit re sponses primarily dependent on store-operated channel (SOC) influx of Ca2+. The duration of transient responses induced by ATP was not significantly d ifferent 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. H owever, the time course of the PAF response at pH 7.4 was significantly red uced by 87% with external pH at 6.2. These results suggest that acidificati on of extracellular solutions inhibits SOC entry of Ca2+ with little or no effect on depletion of ER stores. Changes of extracellular pH over the rang e 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 r apidly 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 th e acid pH inhibition. Since SOC mediated influx of Ca2+ is strongly modulat ed by membrane potential, the electrophysiological data suggest that acidif ication may act to inhibit SOC by cellular depolarization. These results su ggest that acidification observed during cerebral ischemia may alter microg lial responses and functions. (C) 2001 Wiley-Liss, Inc.