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

ABSTRACT: 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 Ca(2+)entry (SOCE), a major Ca(2+)influx pathway, and reduce the Ca(2+)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 Ca(2+)sensor that regulates SOCE. This interaction was modulated by ?1R ligands. After depletion of Ca(2+)stores, ?1R accompanied STIM1 to ER-plasma membrane (PM) junctions where STIM1 stimulated opening of the Ca(2+)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.

SUBMITTER: Srivats S 

PROVIDER: S-EPMC4828687 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature