The TRPCs-STIM1-Orai interaction

Handb Exp Pharmacol. 2014:223:1035-54. doi: 10.1007/978-3-319-05161-1_13.


Ca(2+) signaling entails receptor-stimulated Ca(2+) release from the ER stores that serves as a signal to activate Ca(2+) influx channels present at the plasma membrane, the store-operated Ca(2+) channels (SOCs). The two known SOCs are the Orai and TRPC channels. The SOC-dependent Ca(2+) influx mediates and sustains virtually all Ca(2+)-dependent regulatory functions. The signal that transmits the Ca(2+) content of the ER stores to the plasma membrane is the ER resident, Ca(2+)-binding protein STIM1. STIM1 is a multidomain protein that clusters and dimerizes in response to Ca(2+) store depletion leading to activation of Orai and TRPC channels. Activation of the Orais by STIM1 is obligatory for their function as SOCs, while TRPC channels can function as both STIM1-dependent and STIM1-independent channels. Here we discuss the different mechanisms by which STIM1 activates the Orai and TRPC channels, the emerging specific and non-overlapping physiological functions of Ca(2+) influx mediated by the two channel types, and argue that the TRPC channels should be the preferred therapeutic target to control the toxic effect of excess Ca(2+) influx.

Publication types

  • Review

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Channels / physiology*
  • Humans
  • Membrane Proteins / physiology*
  • Neoplasm Proteins / physiology*
  • ORAI1 Protein
  • Stromal Interaction Molecule 1
  • TRPC Cation Channels / physiology*


  • Calcium Channels
  • Membrane Proteins
  • Neoplasm Proteins
  • ORAI1 Protein
  • ORAI1 protein, human
  • STIM1 protein, human
  • Stromal Interaction Molecule 1
  • TRPC Cation Channels
  • Calcium