Sigma-1 receptor (SIGMAR1) (SIGMAR1)

The Sigma-1 receptor (S1R), historically referred to as the low-affinity opioid binding site, is a unique non-opioid, non-GPCR transmembrane protein primarily localized at the mitochondria-associated endoplasmic reticulum membrane (MAM). Initially misclassified as an opioid receptor subtype due to its affinity for benzomorphans like pentazocine, it is now recognized as a molecular chaperone that regulates protein folding, calcium signaling, and the activity of various ion channels and G protein-coupled receptors. S1R plays a critical role in cellular homeostasis and neuroprotection, and its dysfunction is implicated in several neurodegenerative and psychiatric disorders, including Alzheimer's disease, Parkinson's disease, and major depressive disorder. Pharmacological modulation of S1R by agonists has shown therapeutic potential in enhancing cognitive function and providing neuroprotection, while antagonists are being explored for their analgesic and anti-tumor properties. Key ligands include dextromethorphan, fluvoxamine, and the investigational drug blarcamesine (Anavex 2-73).

Other names

Sigma-1 receptorS1RSigma-1 binding siteLow-affinity opioid binding siteSigma non-opioid intracellular receptor 1SR-BP1OPRS1

Sigma-1 receptor ligands act as molecular chaperone modulators that regulate calcium signaling between the endoplasmic reticulum and mitochondria by interacting with IP3 receptors, and also modulate the activity of various plasma membrane receptors and ion channels.