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


ABSTRACT: 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.

SUBMITTER: Atakpa P 

PROVIDER: S-EPMC6302550 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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IP<sub>3</sub> Receptors Preferentially Associate with ER-Lysosome Contact Sites and Selectively Deliver Ca<sup>2+</sup> to Lysosomes.

Atakpa Peace P   Thillaiappan Nagendra Babu NB   Mataragka Stefania S   Prole David L DL   Taylor Colin W CW  

Cell reports 20181201 11


Inositol 1,4,5-trisphosphate (IP<sub>3</sub>) receptors (IP<sub>3</sub>Rs) allow extracellular stimuli to redistribute Ca<sup>2+</sup> from the ER to cytosol or other organelles. We show, using small interfering RNA (siRNA) and vacuolar H<sup>+</sup>-ATPase (V-ATPase) inhibitors, that lysosomes sequester Ca<sup>2+</sup> released by all IP<sub>3</sub>R subtypes, but not Ca<sup>2+</sup> entering cells through store-operated Ca<sup>2+</sup> entry (SOCE). A low-affinity Ca<sup>2+</sup> sensor target  ...[more]

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