FIGURE 1.

Cell biological roles of sigma-1 receptors (Sig-1R) at the ER. Sig-1R are highly enriched at the mitochondria-associated ER membrane (MAM). Sig-1R is a unique chaperone protein that forms homo-oligomers (i.e., trimmers) and interacts with BiP in its dormant state. Upon binding Sig-1R agonists, which mediate the homo-oligomers’ destabilization, and lead to dissociation of BiP from Sig-1R, Sig-1R is activated to exert its innate chaperone activity. Sig-1R stabilizes IP3 receptors type-3 (IP₃R3) at the MAM, thus regulates Ca²⁺ influx into mitochondria and ATP synthesis. Sig-1R also stabilizes the ER stress sensor IRE1 at the MAM under ER or oxidative stress. Sig-1R thus regulates expression of stress-related proteins by regulating transcription factors XBP-1 and NF-kB. ERAD, ER-associated degradation; ERSE, endoplasmic reticulum stress element.