Sigma-1 receptor and Sigma-2 receptor (S1R/S2R)

The Sigma-1 and Sigma-2 receptors are distinct, non-opioid intracellular proteins that serve as key regulators of cellular proteostasis and lipid metabolism. The Sigma-1 receptor (S1R) functions as a ligand-operated molecular chaperone at the mitochondria-associated endoplasmic reticulum membrane (MAM), where it modulates calcium signaling via the IP3 receptor and protects against ER stress (UniProt Q99720). The Sigma-2 receptor (S2R), recently identified as Transmembrane Protein 97 (TMEM97), is involved in cholesterol homeostasis, lysosomal function, and the regulation of cell proliferation (UniProt Q5BJF2; Alon et al., 2017, PMID: 28559487). Both receptors are widely expressed in the brain and peripheral tissues, and their dysregulation is linked to neurodegenerative diseases, psychiatric conditions, and various cancers (Su et al., 2010, PMID: 20638385). Therapeutic strategies targeting S1R often focus on neuroprotection and cognitive enhancement, while S2R ligands are being investigated for their potential in oncology and the treatment of neuropathic pain.

Other names

Sigma-1 receptorSigma-2 receptorSIGMAR1TMEM97Sigma non-opioid intracellular receptor 1Transmembrane protein 97MAC30SR-BPSR31747

Sigma-1 receptor ligands act as molecular chaperone modulators at the mitochondria-associated ER membrane to regulate calcium signaling and protein folding. Sigma-2 receptor ligands modulate cholesterol trafficking and lysosomal integrity, influencing cell survival and neuroplasticity.