ER-Ca2+ stores and the regulation of store-operated Ca2+ entry in neurons

J Physiol. 2024 Apr;602(8):1463-1474. doi: 10.1113/JP283827. Epub 2023 Feb 4.


Key components of endoplasmic reticulum (ER) Ca2+ release and store-operated Ca2+ entry (SOCE) are likely expressed in all metazoan cells. Due to the complexity of canonical Ca2+ entry mechanisms in neurons, the functional significance of ER-Ca2+ release and SOCE has been difficult to identify and establish. In this review we present evidence of how these two related mechanisms of Ca2+ signalling impact multiple aspects of neuronal physiology and discuss their interaction with the better understood classes of ion channels that are gated by either voltage changes or extracellular ligands in neurons. Given how a small imbalance in Ca2+ homeostasis can have strongly detrimental effects on neurons, leading to cell death, it is essential that neuronal SOCE is carefully regulated. We go on to discuss some mechanisms of SOCE regulation that have been identified in Drosophila and mammalian neurons. These include specific splice variants of stromal interaction molecules, different classes of membrane-interacting proteins and an ER-Ca2+ channel. So far these appear distinct from the mechanisms of SOCE regulation identified in non-excitable cells. Finally, we touch upon the significance of these studies in the context of certain human neurodegenerative diseases.

Keywords: IP3R; Orai; STIM; neurodegeneration.

Publication types

  • Review

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Signaling* / physiology
  • Drosophila / metabolism
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Mammals / metabolism
  • Membrane Proteins* / metabolism
  • Neurons / metabolism
  • ORAI1 Protein
  • Stromal Interaction Molecule 1 / metabolism


  • Stromal Interaction Molecule 1
  • Membrane Proteins
  • Calcium
  • ORAI1 Protein