IP ₃ Receptors Preferentially Associate with ER-Lysosome Contact Sites and Selectively Deliver Ca ²⁺ to Lysosomes

Summary

Inositol 1,4,5-trisphosphate (IP ₃) receptors (IP ₃Rs) allow extracellular stimuli to redistribute Ca ²⁺ 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 Ca ²⁺ released by all IP ₃R subtypes, but not Ca ²⁺ entering cells through store-operated Ca ²⁺ entry (SOCE). A low-affinity Ca ²⁺ sensor targeted to lysosomal membranes reports large, local increases in cytosolic [Ca ²⁺] during IP ₃-evoked Ca ²⁺ release, but not during SOCE. Most lysosomes associate with endoplasmic reticulum (ER) and dwell at regions populated by IP ₃R clusters, but IP ₃Rs do not assemble ER-lysosome contacts. Increasing lysosomal pH does not immediately prevent Ca ²⁺ uptake, but it causes lysosomes to slowly redistribute and enlarge, reduces their association with IP ₃Rs, and disrupts Ca ²⁺ exchange with ER. In a “piston-like” fashion, ER concentrates cytosolic Ca ²⁺ and delivers it, through large-conductance IP ₃Rs, to a low-affinity lysosomal uptake system. The involvement of IP ₃Rs allows extracellular stimuli to regulate Ca ²⁺ exchange between the ER and lysosomes.

Graphical Abstract

Highlights

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  IP ₃ receptors (IP ₃Rs) selectively deliver Ca ²⁺ to lysosomes

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  Lysosomes associate preferentially with clusters of IP ₃Rs in ER membranes

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  Low lysosomal pH maintains the IP ₃R-lysosome contacts required for Ca ²⁺ uptake

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  ER and its Ca ²⁺ channels deliver Ca ²⁺ to low-affinity lysosomal transporters

Abstract

Ca ²⁺ exchanges between ER and lysosomes regulate cytosolic Ca ²⁺ signals and lysosome behavior. Atakpa et al. show that clusters of IP ₃ receptors populate ER-lysosome contact sites and facilitate local delivery of Ca ²⁺ from the ER to lysosomes.