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Direct mobilisation of lysosomal Ca2+ triggers complex Ca2+ signals
Bethan S. Kilpatrick, Emily R. Eden, Anthony H. Schapira, Clare E. Futter, Sandip Patel


Accumulating evidence implicates acidic organelles of the endolysosomal system as mobilisable stores of Ca2+ but their relationship to the better-characterised endoplasmic reticulum (ER) Ca2+ store remains unclear. Here we show that rapid osmotic permeabilisation of lysosomes evokes prolonged, spatiotemporally complex Ca2+ signals in primary cultured human fibroblasts. These Ca2+ signals comprised an initial response that correlated with lysosomal disruption and secondary long-lasting spatially heterogeneous Ca2+ oscillations that required ER-localised inositol trisphosphate receptors. Electron microscopy identified extensive membrane contact sites between lysosomes and the ER. Mobilisation of lysosomal Ca2+ stores is thus sufficient to evoke ER-dependent Ca2+ release probably through lysosome–ER membrane contact sites, and akin to the proposed mechanism of action of the Ca2+ mobilising messenger nicotinic acid adenine dinucleotide phosphate (NAADP). Our data identify functional and physical association of discrete Ca2+ stores important for the genesis of Ca2+ signal complexity.


  • Funding

    This was supported by the Biotechnology and Biological Sciences Research Council [grant number BB/K000942/1 to S.P.], Parkinson’s UK [grant number K-1107 to S.P. and A.H.S.] and an IMPACT studentship from University College London [to B.S.K.].

  • Accepted October 17, 2012.
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