Interactions between the G Protein‐coupled Estrogen Receptor and the Stromal Interaction Molecule 1

The G protein‐coupled estrogen receptor (GPER/GPR30) participates in various Ca 2+ ‐dependent cellular functions, yet its direct effects and mechanisms on components of Ca 2+ signaling machinery are incompletely understood. Store‐operated Ca 2+ entry (SOCE) is an essential Ca 2+ signaling mechanism that regulates numerous cellular activities. Here we show that GPER/GPR30 expression and activation limits SOCE. Heterologous expression and gene silencing studies demonstrated that GPER/GPR30's expression puts a constitutive break on SOCE. Co‐immunoprecipitation and confocal microscopy studies indicated that GPER/GPR30 interacts with the stromal interaction molecule 1 (STIM1) at different interaction sites in distinct subcellular compartments. Pharmacological studies indicated that GPER/GPR30 activation acutely further suppresses SOCE in addition to the effect of physical interaction between GPER/GPR30 and STIM1. Site‐directed mutagenesis studies indicated that GPER/GPR30 activation inhibits SOCE via alteration in the phosphorylation status of STIM1. Taken together, the data demonstrate physical and functional interactions as mechanisms whereby GPER/GPR30 expression and activation regulates SOCE. Support or Funding Information NIH HL112184 (to KT)