GPER/GPR30 and Components of Store‐operated Ca 2+ entry

The novel G protein‐coupled estrogen receptor 1 (GPER/GPR30) has been found to participate in numerous cardiovascular functions. Store‐operated Ca 2+ entry (SOCE) is an essential mechanism required for many cell activities. We found that GPER agonist G‐1 inhibits SOCE in endothelial cells. Heterologous expression of GPER causes a 40% decrease in the rate of SOCE. GPER antagonist G15 acutely increases rates of SOCE by 16% and when treated chronically, increases total Ca 2+ signals by 50% in vascular smooth muscle. Consistently, GPER gene silencing increases SOCE by approximately 50%. In endothelial and ventricular tissues, GPER coimmunoprecipitates with the stromal interaction molecule 1 (Stim1) and the sarcoplasmic reticulum Ca 2+ ‐ATPase (SERCA), two essential molecular switchers of SOCE. In addition, Stim1 colocalizes with GPER when heterologously expressed in HEK 293 cells. In addition, overexpression of GPER substantially reduces thapsigargin‐induced Ca 2+ release from the endoplasmic reticulum in vascular endothelial cells, an indication of reduced SERCA activity. These data suggest that GPER may be an important regulatory input of store‐operated Ca 2+ entry via its interactions with key components of store‐operated Ca 2+ entry.