8.A.93. The Sigma2 Receptor or TMEM97 (S2R) Family
The endoplasmic reticulum (ER) TMEM97 protein (the sigma2 or σ2 receptor) of 176 aas and 4 predicted TMSs (TC#8.A.93.1.1) has both N- and C-termini in the cytoplasm. It has an ER targetting sequence and is an ER resident protein that regulates the sterol transporter, NPC1 (TC# 2.A.6.6.1) (Maxfield et al. 2016). It is involved in diseases as diverse as cancer and neurological disorders (Alon et al. 2017). It has been associated with cholesterol homeostasis and has been implicated in Niemann–Pick disease (Kim and Pasternak 2017). TMEM97 possesses the full suite of molecular properties that define the sigma2 receptor, and Asp29 and Asp56 are essential for ligand recognition (Alon et al. 2017). These two aspartate residues are predicted to reside near the ER luminal surface.
A human homologue, Tm6sf1, is present in lysosomal membranes. Fusion of Tm6sf1 vesicles with lysosomes and the integration of Tm6sf1 into the lysosomal membrane has been demonstrated (Tam et al. 2015). The protein is expressed in mouse tissues in major organs such as the cerebellum, kidney and intestine. The sigma2R/TMEM97 small molecule modulator, JVW-1034, reduces heavy alcohol drinking and associated pain states in male mice (Quadir et al. 2020).
There are two known subtypes of the so-called sigma receptors, Sigma1 and Sigma2. Sigma1 (encoded by the SIGMAR1 gene and also known as Sigma-1 receptor, S1R) is a unique pharmacologically regulated integral membrane chaperone or scaffolding protein that allosterically modulates the activity of its associated proteins. Sigma2, transmembrane protein 97 (TMEM97), is an integral membrane protein implicated in cellular cholesterol homeostasis, playing a role for both sigma proteins in tumor biology. A growing body of evidence supports the potential of small-molecule compounds with affinity for these proteins, putative sigma ligands, as therapeutic agents to treat cancer. These compounds inhibit cancer cell proliferation, survival, adhesion, and migration, and they suppress tumor growth, to alleviate cancer-associated pain, and to exert immunomodulatory properties (Oyer et al. 2019).