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

J Cell Sci. 2016 Oct 15;129(20):3903-3910. doi: 10.1242/jcs.191585. Epub 2016 Sep 2.


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.

Keywords: Ca2+ signalling; Drosophila; IP3 receptor; Orai; STIM; Store-operated Ca2+ entry.

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium Signaling
  • Cell Membrane / metabolism
  • Chickens
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / metabolism*
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • Models, Biological
  • Mutant Proteins / metabolism*
  • Neurons / metabolism*
  • ORAI1 Protein / metabolism*
  • Stromal Interaction Molecule 1 / metabolism*
  • Vertebrates / metabolism


  • Drosophila Proteins
  • Inositol 1,4,5-Trisphosphate Receptors
  • Mutant Proteins
  • ORAI1 Protein
  • Stim protein, Drosophila
  • Stromal Interaction Molecule 1
  • olf186-F protein, Drosophila
  • Calcium