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

Sigma1 receptors (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 1Rs exert such varied effects. We demonstrate that 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 1R or an agonist of 1R and enhanced by loss of 1R or an antagonist. Within the endoplasmic reticulum (ER), 1R associated with STIM1, the ER Ca²⁺ sensor that regulates SOCE. This interaction was modulated by 1R ligands. After depletion of Ca²⁺ stores, 1R accompanied STIM1 to ER–plasma membrane (PM) junctions where STIM1 stimulated opening of the Ca²⁺ channel, Orai1. The association of STIM1 with 1R slowed the recruitment of STIM1 to ER–PM junctions and reduced binding of STIM1 to PM Orai1. We conclude that 1R attenuates STIM1 coupling to Orai1 and thereby inhibits SOCE.

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