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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. There is a link between TMEM97 and chronic inflammation in obesity in adipose tissue and skeletal muscle (Tenta et al. 2022).

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). TMEM97 is transcriptionally activated by YY1 and promotes colorectal cancer progression via the GSK-3beta/beta-catenin signaling pathway (Mao et al. 2022).

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).

References associated with 8.A.93 family:

Alon, A., H.R. Schmidt, M.D. Wood, J.J. Sahn, S.F. Martin, and A.C. Kruse. (2017). Identification of the gene that codes for the σ2 receptor. Proc. Natl. Acad. Sci. USA. [Epub: Ahead of Print] 28559337
Di Sessa, A., S. Guarino, A.P. Passaro, L. Liguori, G.R. Umano, G. Cirillo, E. Miraglia Del Giudice, and P. Marzuillo. (2021). NAFLD and renal function in children: is there a genetic link? Expert Rev Gastroenterol Hepatol 1-10. [Epub: Ahead of Print] 33851883
Ehrhardt, N., M.E. Doche, S. Chen, H.Z. Mao, M.T. Walsh, C. Bedoya, M. Guindi, W. Xiong, J. Ignatius Irudayam, J. Iqbal, S. Fuchs, S.W. French, M. Mahmood Hussain, M. Arditi, V. Arumugaswami, and M. Péterfy. (2017). Hepatic Tm6sf2 overexpression affects cellular ApoB-trafficking, plasma lipid levels, hepatic steatosis and atherosclerosis. Hum Mol Genet 26: 2719-2731. 28449094
Intagliata, S., A. Sharma, T.I. King, C. Mesangeau, M. Seminerio, F.T. Chin, L.L. Wilson, R.R. Matsumoto, J.P. McLaughlin, B.A. Avery, and C.R. McCurdy. (2020). Discovery of a Highly Selective Sigma-2 Receptor Ligand, 1-(4-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (CM398), with Drug-Like Properties and Antinociceptive Effects In Vivo. AAPS J 22: 94. 32691179
Kim, F.J. and G.W. Pasternak. (2017). Cloning the sigma2 receptor: Wandering 40 years to find an identity. Proc. Natl. Acad. Sci. USA. [Epub: Ahead of Print] 28645899
Kim, F.J., I. Kovalyshyn, M. Burgman, C. Neilan, C.C. Chien, and G.W. Pasternak. (2010). Sigma 1 receptor modulation of G-protein-coupled receptor signaling: potentiation of opioid transduction independent from receptor binding. Mol Pharmacol 77: 695-703. 20089882
Lee, K.J., J.S. Moon, N.Y. Kim, and J.S. Ko. (2022). Effects of PNPLA3, TM6SF2 and SAMM50 on the development and severity of non-alcoholic fatty liver disease in children. Pediatr Obes 17: e12852. 34490745
Li, T.T., T.H. Li, J. Peng, B. He, L.S. Liu, D.H. Wei, Z.S. Jiang, X.L. Zheng, and Z.H. Tang. (2018). TM6SF2: A novel target for plasma lipid regulation. Atherosclerosis 268: 170-176. 29232562
Longo, M., M. Meroni, E. Paolini, V. Erconi, F. Carli, F. Fortunato, D. Ronchi, R. Piciotti, S. Sabatini, C. Macchi, A. Alisi, L. Miele, G. Soardo, G.P. Comi, L. Valenti, M. Ruscica, A.L. Fracanzani, A. Gastaldelli, and P. Dongiovanni. (2021). TM6SF2/PNPLA3/MBOAT7 Loss-of-Function Genetic Variants Impact on NAFLD Development and Progression Both in Patients and in In Vitro Models. Cell Mol Gastroenterol Hepatol 13: 759-788. [Epub: Ahead of Print] 34823063
Mao, D., X. Zhang, Z. Wang, G. Xu, and Y. Zhang. (2022). TMEM97 is transcriptionally activated by YY1 and promotes colorectal cancer progression via the GSK-3β/β-catenin signaling pathway. Hum Cell 35: 1535-1546. 35907137
Maxfield, F.R., D.B. Iaea, and N.H. Pipalia. (2016). Role of STARD4 and NPC1 in intracellular sterol transport. Biochem. Cell Biol. 94: 499-506. 27421092
Oyer, H.M., C.M. Sanders, and F.J. Kim. (2019). Small-Molecule Modulators of Sigma1 and Sigma2/TMEM97 in the Context of Cancer: Foundational Concepts and Emerging Themes. Front Pharmacol 10: 1141. 31695608
Quadir, S.G., S.M. Tanino, C.D. Rohl, J.J. Sahn, E.J. Yao, L.D.R. Cruz, P. Cottone, S.F. Martin, and V. Sabino. (2020). The Sigma-2 receptor / transmembrane protein 97 (σ2R/TMEM97) modulator JVW-1034 reduces heavy alcohol drinking and associated pain states in male mice. Neuropharmacology 108409. [Epub: Ahead of Print] 33221481
Rivera-Iñiguez, I., A. Panduro, S. Roman, and K. González-Aldaco. (2022). What do we know about nutrient-based strategies targeting molecular mechanisms associated with obesity-related fatty liver disease? Ann Hepatol 28: 100874. [Epub: Ahead of Print] 36371078
Schmidt, H.R., S. Zheng, E. Gurpinar, A. Koehl, A. Manglik, and A.C. Kruse. (2016). Crystal structure of the human σ1 receptor. Nature 532: 527-530. 27042935
Tam, W.Y., L. Jiang, and K.M. Kwan. (2015). Transmembrane 6 superfamily 1 (Tm6sf1) is a novel lysosomal transmembrane protein. Protoplasma 252: 977-983. 25422095
Tenta, M., J. Eguchi, and J. Wada. (2022). Roles of Transmembrane Protein 97 (TMEM97) in Adipose Tissue and Skeletal Muscle. Acta Med Okayama 76: 235-245. 35790353
Thomas, J.D., C.G. Longen, H.M. Oyer, N. Chen, C.M. Maher, J.M. Salvino, B. Kania, K.N. Anderson, W.F. Ostrander, K.E. Knudsen, and F.J. Kim. (2017). Sigma1 Targeting to Suppress Aberrant Androgen Receptor Signaling in Prostate Cancer. Cancer Res 77: 2439-2452. 28235766
Yousuf, M.S., J.J. Sahn, E.T. David, S. Shiers, D.M. Royer, C.D. Garcia, J. Zhang, V.M. Hong, A. Ahmad, B.J. Kolber, D.J. Liebl, S.F. Martin, and T.J. Price. (2023). Validation of σ R/TMEM97 as a neuropathic pain target: Specificity, human expression and mechanism of action. bioRxiv. 37090527
Yousuf, M.S., J.J. Sahn, H. Yang, E.T. David, S. Shiers, M. Mancilla Moreno, J. Iketem, D.M. Royer, C.D. Garcia, J. Zhang, V.M. Hong, S.M. Mian, A. Ahmad, B.J. Kolber, D.J. Liebl, S.F. Martin, and T.J. Price. (2023). Highly specific σR/TMEM97 ligand FEM-1689 alleviates neuropathic pain and inhibits the integrated stress response. Proc. Natl. Acad. Sci. USA 120: e2306090120. 38117854