The Sigma-1 Receptor in Cellular Stress Signaling

After decades of research, the sigma-1 receptor (Sig-1R)'s structure, and molecular functions are being unveiled. Sig-1R is an integral endoplasmic reticulum (ER) membrane protein which forms an oligomer and binds a variety of psychotropic drugs. It forms a complex with the ER chaperone BiP that controls specific signaling molecules' stability and function at the ER to regulate Ca²⁺ signaling, bioenergetics, and ER stress. Sig-1R is highly enriched in ER subdomains that are physically linked to outer mitochondrial membranes, reflecting its role in regulating ER-mitochondria communications. Thus, Sig-1R ligands are expected to serve as novel neuroprotective agents which treat certain psychiatric and neurodegenerative disorders. In this short review, the cell biological aspects of Sig-1R are discussed, with a particular focus on its role in fundamental ER functions.