Does lysosomal rupture evoke Ca2+ release? A question of pores and stores

Abstract Lysosomotropic agents have been used to permeabilize lysosomes and thereby implicate these organelles in diverse cellular processes. Since lysosomes are Ca2+ stores, this rupturing action, particularly that induced by GPN, has also been used to rapidly release Ca2+ from lysosomes. However, a recent study has questioned the mechanism of action of GPN and concluded that, acutely, it does not permeabilize lysosomes but releases Ca2+ directly from the ER instead. We therefore appraise these provocative findings in the context of the existing literature. We suggest that further work is required to unequivocally rule out lysosomes as contributors to GPN-evoked Ca2+ signals.