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Identification of the gene that codes for the σ 2 receptor
Abstract
Significance: Of the many receptors that were pharmacologically described during the 20th century, almost all were cloned by the end of the 1990s. A key exception is the σ 2 receptor, a potential therapeutic target for diseases as diverse as schizophrenia, Alzheimer’s disease, and cancer. Despite the development of a rich pharmacopeia, the unknown molecular identity of the receptor has crippled biological investigation. Here, we identify the σ 2 receptor as TMEM97, a membrane protein implicated in cancer and a binding partner of Niemann–Pick disease protein NPC1. Our results unite two fields of research, bringing the σ 2 receptor into the modern age of biological inquiry and providing the TMEM97 field with a rich pool of ligands and pharmacological tools.
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TMEM97 was recently identified as the gene that codes for the Sigma-2 receptor.
“TMEM97 was recently identified as the gene that codes for the Sigma-2 receptor [3].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [3]
The recent identification of the σ2R as TMEM97 provided further support to the absence of any correlation between the σ2R and PGRMC1.
“The recent identification of the σ2R as being the protein, TMEM97, provided further support to the absence of any correlation between the σ2R, now called the TMEM97/σ2R, and PGRMC119,21.”
From Sigma-2 Receptor/TMEM97 and PGRMC-1 Increase the Rate of Internalization of LDL by LDL Receptor through the Formation of a Ternary Complex (2018) · cites this paper as [19]
TMEM97 is thought to be involved in cholesterol trafficking through its association with lysosomal cholesterol transporter NPC1.
“TMEM97 is thought to be involved in cholesterol trafficking through its association with lysosomal cholesterol transporter NPC1, a protein whose loss results in a fatal lysosomal storage disorder, Niemann–Pick disease type C119.”
From Sigma-2 Receptor/TMEM97 and PGRMC-1 Increase the Rate of Internalization of LDL by LDL Receptor through the Formation of a Ternary Complex (2018) · cites this paper as [19]
The sigma-2 receptor (S2R) is encoded by TMEM97, and S2R and TMEM97 are one and the same.
“In 2017, the S2R was cloned [61], demonstrating that TMEM97, not PGRMC1, was the gene encoding S2R, indicating that S2R and TMEM97 are one and the same.”
From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [61]
Reduction or ablation of S2R activity was observed when TMEM97 expression was reduced or absent in calf liver cells or human cervical cancer cells.
“This was confirmed in pharmacological studies assessing the activity of S2R ligands where reduction, or ablation, of S2R activity was observed when TMEM97 expression was reduced, or absent, in calf liver cells [16,61] or human cervical cancer cells [66], respectively.”
From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [61]
The crystal structure added additional confirmation that S2R is structurally distinct from the sigma-1 receptor.
“This crystal structure also added additional confirmation that S2R is structurally distinct from the sigma-1 receptor [16,61,68].”
From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [61]
In tumor cells, the canonical Sigma-2 ligand DTG binds to Sigma-2 receptors at a location on the TMEM97 protein.
“In tumor cells, the canonical Sigma-2 ligand DTG binds to Sigma-2 receptors at a location on the TMEM97 protein [3]”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [3]
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Structures of the σ2 receptor enable docking for bioactive ligand discovery
Alon, A., Lyu, J., Braz, J. M., Tummino, T. A., Craik, V., O’Meara, M. J., Webb, C. M., Radchenko, D. S., Moroz, Y. S., Huang, X.-P., et al. (2021) · Nature · doi:10.1038/s41586-021-04175-x · Cited by 211
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Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease
Colom-Cadena, M., Toombs, J., Simzer, E., Holt, K., McGeachan, R., Tulloch, J., Jackson, R. J., Catterson, J. H., Spires-Jones, M. P., Rose, J., et al. (2024) · Acta Neuropathologica · doi:10.1007/s00401-023-02679-6 · Cited by 44
Metadata
- Authors
- Alon, A., Schmidt, H. R., Wood, M. D., Sahn, J. J., Martin, S. F., & Kruse, A. C.
- Affiliations
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
- Department of Chemistry, The University of Texas at Austin, Austin, TX 78712
- ORCID
- Kruse, Andrew C.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-05-30
- Volume
- 114
- Issue
- 27
- Pages
- 7160-7165
- ISSN
- 0027-8424
- 1091-6490
- Cited by
- 267
- References
- 5
- Language
- en
- Funders
- HHS | National Institutes of Health (1DP5OD021345)
- Vallee Foundation (N/A)
- Harvard Brain Science Initiative (N/A)
- Esther A. and Joseph Klingenstein Fund (N/A)
- Welch Foundation (F-0652)
- National Science Foundation (N/A)
- BrightFocus Foundation (N/A)
- Texas Health Catalyst Program (N/A)
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