A computational model of lysosome-ER Ca2+ microdomains.
Acidic organelles form an important intracellular Ca(2+) pool that can drive global Ca(2+) signals through coupling with endoplasmic reticulum (ER) Ca(2+) stores. Recently identified lysosome-ER membrane contact sites might allow formation of Ca(2+) microdomains, although their size renders observation of Ca(2+) dynamics impractical. Here, we generated a computational model of lysosome-ER coupling that incorporated a previous model of the inositol trisphosphate (IP3) receptor as the ER Ca(2+) 'amplifier' and lysosomal leaks as the Ca(2+) 'trigger'. The model qualitatively described global Ca(2+) responses to the lysosomotropic agent GPN, which caused a controlled but substantial depletion of small solutes from the lysosome. Adapting this model to physiological lysosomal leaks induced by the Ca(2+) mobilising messenger NAADP demonstrated that lysosome-ER microdomains are capable of driving global Ca(2+) oscillations. Interestingly, our simulations suggest that the microdomain [Ca(2+)] need not be higher than that in the cytosol for responses to occur, thus matching the relatively high affinity of IP3 receptors for Ca(2+). The relative distribution and overall density of the lysosomal leaks dictated whether microdomains triggered or modulated global signals. Our data provide a computational framework for probing lysosome-ER Ca(2+) dynamics.
Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
Christopher J
CJ
Penny
Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
Bethan S
BS
Kilpatrick
Department of Mathematics, University of Auckland, Auckland 1142, New Zealand.
Jung Min
JM
Han
Department of Mathematics, University of Auckland, Auckland 1142, New Zealand.
James
J
Sneyd
Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK patel.s@ucl.ac.uk.
Sandip
S
Patel
D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism; D003629:Modems; D009249:NADP / Q000031:analogs & derivatives* / Q000378:metabolism
D015220:Calcium Channels; D009249:NADP; C024376:NAADP; D002118:Calcium
Ca2+; Computational modelling; Endoplasmic reticulum; Lysosomes; Membrane contact site; NAADP; Two-pore channel