Mutant IP3 receptors attenuate store-operated Ca2+ entry by destabilizing STIM-Orai interactions in Drosophila neurons

Abstract

Store-operated Ca2+ entry (SOCE) occurs when loss of Ca2+ from the endoplasmic reticulum (ER) stimulates the Ca2+ sensor, STIM, to cluster and activate the plasma membrane (PM) Ca2+ channel, Orai. Inositol 1,4,5-trisphosphate receptors (IP3R) are assumed to regulate SOCE solely by mediating ER Ca2+ release. We show that in Drosophila neurons, mutant IP3R attenuate SOCE evoked by depleting Ca2+ stores with thapsigargin. In normal neurons, store depletion caused STIM and IP3R to accumulate near the PM, association of STIM with Orai, clustering of STIM and Orai at ER-PM junctions, and activation of SOCE. These responses were attenuated in neurons with mutant IP3R and rescued by over-expression of STIM with Orai. We conclude that after depletion of Ca2+ stores in Drosophila, translocation of IP3R to ER-PM junctions facilitates the coupling of STIM to Orai that leads to activation of SOCE.