GPN does not release lysosomal Ca 2+ but evokes Ca 2+ release from the ER by increasing the cytosolic pH independently of cathepsin C.

Autor: Atakpa P; Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK., van Marrewijk LM; Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK., Apta-Smith M; Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK., Chakraborty S; Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK., Taylor CW; Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK cwt1000@cam.ac.uk.
Jazyk: angličtina
Zdroj: Journal of cell science [J Cell Sci] 2019 Feb 01; Vol. 132 (3). Date of Electronic Publication: 2019 Feb 01.
DOI: 10.1242/jcs.223883
Abstrakt: 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.
Competing Interests: Competing interestsThe authors declare no competing or financial interests.
(© 2019. Published by The Company of Biologists Ltd.)
Databáze: MEDLINE
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