Sigmal receptors inhibit store-operated Ca2+ entry by attenuating coupling of STIM1 to Orail

Sigma] receptors (sigma 1Rs) 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 sigma 1Rs exert such varied effects. We demonstrate that sigma 1Rs 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 al R or an agonist of al R and enhanced by loss of al R or an antagonist. Within the endoplasmic reticulum (ER), al R associated with STIM1, the ER Ca2+ sensor that regulates SOCE. This interaction was modulated by al R ligands. After depletion of Ca2+ stores, al R accompanied STIM1 to ER plasma membrane (PM) junctions where STIM1 stimulated opening of the Ca2+ channel, Orail. The association of STIM1 with al R slowed the recruitment of STIM1 to ER PM junctions and reduced binding of STIM1 to PM Orail. We conclude that al R attenuates STIM1 coupling to Orail and thereby inhibits SOCE.