Sigma-2 receptor (Transmembrane protein 97) (Sigma-2R)

The Sigma-2 receptor, recently identified as Transmembrane protein 97 (TMEM97), is a four-pass transmembrane protein primarily localized in the endoplasmic reticulum and lipid rafts (Alon et al., 2017, Nature Communications). It plays a critical role in regulating cholesterol homeostasis through its interaction with the LDL receptor and the Niemann-Pick C1 (NPC1) protein, facilitating the internal transport of lipids (Riad et al., 2020, Scientific Reports). In oncology, the Sigma-2 receptor is significantly upregulated in various proliferating tumors, such as breast and pancreatic cancer, where its activation by agonists can trigger cell death via apoptotic and lysosomal pathways (Mach et al., 2013, Journal of Medicinal Chemistry). In the central nervous system, Sigma-2 receptor antagonists, such as CT1812, are being investigated for the treatment of Alzheimer's disease because they competitively inhibit the binding of toxic amyloid-beta oligomers to neuronal synapses, thereby preventing synaptic loss (Izzo et al., 2014, Alzheimer's & Dementia). While some classical antipsychotics like haloperidol bind to this receptor, atypical antipsychotics like olanzapine show negligible affinity, which likely explains the specific exclusion note in the target name. The receptor's involvement in both lipid metabolism and cell survival signaling makes it a high-interest target for both diagnostic imaging and therapeutic intervention in cancer and neurodegeneration.

Other names

TMEM97MAC30Transmembrane protein 97Sigma-2S2R

Sigma-2 receptor ligands act as agonists to induce apoptosis and lysosomal membrane permeabilization in cancer cells, or as antagonists to competitively inhibit the binding of neurotoxic amyloid-beta oligomers to neurons in neurodegenerative diseases.