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Department of Pharmacology

Taylor, CW, Atakpa, P, Van Marrewijk, L, Smith, M, Chakraborty, S

GPN (glycyl-L-phenylalanine 2-naphthylamide) 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 (pHly), and transient increases in cytosolic pH (pHcyt) and Ca2+ concentration ([Ca2+]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 [Ca2+]c require Ca2+ within the ER, but they are not mediated by ER Ca2+ channels amplifying Ca2+ release from lysosomes. GPN increases [Ca2+]c by increasing pHcyt, which then directly stimulates Ca2+ release from the ER. We conclude that physiologically relevant increases in pHcyt stimulate Ca2+ release from the ER independent of IP3 and ryanodine receptors, and that GPN does not selectively target lysosomes.

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Published date: 
20 December 2018 (Accepted for publication)
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Publication type: 
Journal articles
Journal name: 
Journal of Cell Science
Publication volume: 
The Company of Biologists Ltd.
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