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IP3 Receptors Preferentially Associate with ER-Lysosome Contact Sites and Selectively Deliver Ca2+ to Lysosomes.

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Atakpa, Peace 
Thillaiappan, Nagendra Babu 
Mataragka, Stefania 
Prole, David L 
Taylor, Colin W 


Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) allow extracellular stimuli to redistribute Ca2+ from the ER to cytosol or other organelles. We show, using small interfering RNA (siRNA) and vacuolar H+-ATPase (V-ATPase) inhibitors, that lysosomes sequester Ca2+ released by all IP3R subtypes, but not Ca2+ entering cells through store-operated Ca2+ entry (SOCE). A low-affinity Ca2+ sensor targeted to lysosomal membranes reports large, local increases in cytosolic [Ca2+] during IP3-evoked Ca2+ release, but not during SOCE. Most lysosomes associate with endoplasmic reticulum (ER) and dwell at regions populated by IP3R clusters, but IP3Rs do not assemble ER-lysosome contacts. Increasing lysosomal pH does not immediately prevent Ca2+ uptake, but it causes lysosomes to slowly redistribute and enlarge, reduces their association with IP3Rs, and disrupts Ca2+ exchange with ER. In a "piston-like" fashion, ER concentrates cytosolic Ca2+ and delivers it, through large-conductance IP3Rs, to a low-affinity lysosomal uptake system. The involvement of IP3Rs allows extracellular stimuli to regulate Ca2+ exchange between the ER and lysosomes.



Ca(2+), IP(3) receptor, concanamycin A, endoplasmic reticulum, genetically encoded Ca(2+) sensor, lysosome, membrane contact site, proximity ligation assay, store-operated Ca(2+) entry, Calcium, Calcium Signaling, Cytosol, Endoplasmic Reticulum, HEK293 Cells, HeLa Cells, Humans, Hydrogen-Ion Concentration, Inositol 1,4,5-Trisphosphate Receptors, Lysosomes

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Elsevier BV
Wellcome Trust (101844/Z/13/Z)
Biotechnology and Biological Sciences Research Council (BB/P005330/1)