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The dipeptide glycyl-l-phenylalanine 2-naphthylamide (GPN) is widely used to perturb lysosomes because its cleavage by the lysosomal enzyme cathepsin C is proposed to rupture lysosomal membranes. We show that GPN evokes a sustained increase in lysosomal pH (pH ly ), and transient increases in cytosolic pH (pH cyt ) and Ca 2+ concentration ([Ca 2+ ] c ). None of these effects require cathepsin C, nor are they accompanied by rupture of lysosomes, but they are mimicked by structurally unrelated weak bases. GPN-evoked increases in [Ca 2+ ] c require Ca 2+ within the endoplasmic reticulum (ER), but they are not mediated by ER Ca 2+ channels amplifying Ca 2+ release from lysosomes. GPN increases [Ca 2+ ] c by increasing pH cyt , which then directly stimulates Ca 2+ release from the ER. We conclude that physiologically relevant increases in pH cyt stimulate Ca 2+ release from the ER in a manner that is independent of IP 3 and ryanodine receptors, and that GPN does not selectively target lysosomes.

GPN does not release lysosomal Ca2+ but evokes Ca2+ release from the ER by increasing the cytosolic pH independently of cathepsin C