Sigma1 receptors inhibit store-operated Ca2+entry by attenuating coupling of STIM1 to Orai1

Sigma1 receptors (s1Rs) are expressed widely; they bind diverse ligands, including psychotropic drugs and steroids, regulate many ion channels, and are implicated in cancer and addiction. It is not known how s1Rs exert such varied effects. We demonstrate that s1Rs inhibit store-operated Ca2+ entry (SOCE), a major Ca2+ influx pathway, and reduce the Ca2+ content of the intracellular stores. SOCE was inhibited by expression of s1R or an agonist of s1R, and enhanced by loss of s1R or an antagonist. Within the endoplasmic reticulum (ER), s1R associated with STIM1, the ER Ca2+-sensor that regulates SOCE. This interaction was modulated by s1R ligands. After depletion of Ca2+ stores, s1R accompanied STIM1 to ER-plasma membrane (PM) junctions where STIM1 stimulated opening of the Ca2+ channel, Orai1. The association of STIM1 with s1R slowed the recruitment of STIM1 to ER-PM junctions and reduced binding of STIM1 to PM Orai1. We conclude that s1R attenuates STIM1 coupling to Orai1, and thereby inhibits SOCE.