title: Endo-lysosomal TRP mucolipin-1 channels trigger global ER Ca2+ release and Ca2+ influx.
abstract: Transient receptor potential (TRP) mucolipins (TRPMLs), encoded by the MCOLN genes, are patho-physiologically relevant endo-lysosomal ion channels crucial for membrane trafficking. Several lines of evidence suggest that TRPMLs mediate localised Ca2+release but their role in Ca2+signalling is not clear. Here, we show that activation of endogenous and recombinant TRPMLs with synthetic agonists evoked global Ca2+signals in human cells. These signals were blocked by a dominant-negative TRPML1 construct and a TRPML antagonist. We further show that, despite a predominant lysosomal localisation, TRPML1 supports both Ca2+release and Ca2+entry. Ca2+release required lysosomal and ER Ca2+stores suggesting that TRPMLs, like other endo-lysosomal Ca2+channels, are capable of 'chatter' with ER Ca2+channels. Our data identify new modalities for TRPML1 action.
authors: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors: Bethan S
authors: BS
authors: Kilpatrick
authors: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors: Elizabeth
authors: E
authors: Yates
authors: Center for Integrated Protein Science CIPSM and Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, München 81377, Germany.
authors: Christian
authors: C
authors: Grimm
authors: Department of Clinical Neurosciences, Institute of Neurology, University College London, London NW3 2PF, UK.
authors: Anthony H
authors: AH
authors: Schapira
authors: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK patel.s@ucl.ac.uk.
authors: Sandip
authors: 0000-0001-7247-2013
authors: S
authors: Patel
mesh_terms: D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D010797:Phthalimides / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000378:metabolism*
chemical_list: C416674:MCOLN1 protein, human; C000599935:ML-SA1 compound; D010797:Phthalimides; D011804:Quinolines; D050051:Transient Receptor Potential Channels; D002118:Calcium
keywords: Ca2+; Endoplasmic reticulum; Lysosomes; TRP channels