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

• Main Authors: Peace Atakpa, Nagendra Babu Thillaiappan, Stefania Mataragka, David L. Prole, Colin W. Taylor
• Format: Article
• Language: English
• Published: Elsevier 2018-12-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124718318400

Summary: 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. : Ca2+ exchanges between ER and lysosomes regulate cytosolic Ca2+ signals and lysosome behavior. Atakpa et al. show that clusters of IP3 receptors populate ER-lysosome contact sites and facilitate local delivery of Ca2+ from the ER to lysosomes. Keywords: Ca2+, concanamycin A, endoplasmic reticulum, IP3 receptor, genetically encoded Ca2+ sensor, lysosome, membrane contact site, proximity ligation assay, store-operated Ca2+ entry