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

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 Ca²⁺ channel Orai (encoded by Olf186-F in flies). Inositol 1,4,5-trisphosphate receptors (IP₃Rs, which are encoded by a single gene in flies) are assumed to regulate SOCE solely by mediating ER Ca²⁺ release. We show that in Drosophila neurons, mutant IP₃R attenuates SOCE evoked by depleting Ca²⁺ stores with thapsigargin. In normal neurons, store depletion caused STIM and the IP₃R to accumulate near the plasma membrane, association of STIM with Orai, clustering of STIM and Orai at ER-plasma-membrane junctions and activation of SOCE. These responses were attenuated in neurons with mutant IP₃Rs and were rescued by overexpression of STIM with Orai. We conclude that, after depletion of Ca²⁺ stores in Drosophila, translocation of the IP₃R to ER-plasma-membrane junctions facilitates the coupling of STIM to Orai that leads to activation of SOCE.

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