The sensitivity of store-operated Ca2+-entry to changes in the extra-and intracellular pH (pH(o) and pH(i), respectively) was investigated in SH-SY5Y human neuroblastoma cells. The intracellular Ca2+-stores were depleted either with I mM carbachol (CCH) or with 2 mu M thapsigargin (TG). Extracellular acidification suppressed both the CCH-and TG-mediated Ca2+-entry while external alkalinization augmented both the CCH- and the TG-induced Ca2+-influx. Mn2+-quenching experiments revealed that the rates of Ca2+-entry at the thapsigargin- or carbachol-induced plateau were both accelerated at pH(o) 8.2 and slowed down at pH(o) 6.8 with respect to the control at pH(o) 7.4. Alteration of pH(o) between 6.8 and 8.2 did not have any significant prompt effect on pH(i) and changes in pH(i) left the CCH-induced Ca2+-entry unaffected. These findings demonstrate that physiologically relevant changes in pH(o) affect the store-operated Ca2+-entry in SH-SY5Y cells and suggest that endogenous pH(o) shifts may regulate cell activity in situ via modulating the store-operated Ca2+-entry. (c) 2005 Elsevier Inc. All rights reserved.