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Lysosomes are acidic Ca 2+  stores often mobilised in conjunction with endoplasmic reticulum (ER) Ca 2+  stores. Glycyl-L-phenylalanine 2-naphthylamide (GPN) is a widely used lysosomotropic agent that evokes cytosolic Ca 2+  signals in many cells. However, whether these signals are the result of a primary action on lysosomes is unclear in light of recent evidence showing that GPN mediates direct ER Ca 2+  release through changes in cytosolic pH. Here, we show that GPN evoked rapid increases in cytosolic pH but slower Ca 2+  signals. NH 4 Cl evoked comparable changes in pH but failed to affect Ca 2+ . The V-type ATPase inhibitor, bafilomycin A1, increased lysosomal pH over a period of hours. Acute treatment modestly affected lysosomal pH and potentiated Ca 2+  signals evoked by GPN. In contrast, chronic treatment led to more profound changes in luminal pH and selectively inhibited GPN action. GPN blocked Ca 2+  responses evoked by the novel nicotinic acid adenine dinucleotide phosphate-like agonist, TPC2-A1-N. Therefore, GPN-evoked Ca 2+  signals were better correlated with associated pH changes in the lysosome compared to the cytosol, and were coupled to lysosomal Ca 2+  release. We conclude that Ca 2+  signals evoked by GPN most likely derive from acidic organelles.

The lysosomotrope GPN mobilises Ca2+ from acidic organelles