The current study demonstrates that the human neuroblastoma SH-SY5Y cells endogenously express G protein-coupled estrogen receptor (GPER) and activation of GPER may induce a rapid increase in cytosolic Ca2+, which is due to PLC/IP3-dependent store Ca2+ release and is followed by PKC activation and MOR phosphorylation. Here, OPRM1 is linked to neuroblastoma.