Sigma-2 receptor

TMEM97
Identifiers
AliasesTMEM97, MAC30, transmembrane protein 97, Sigma-2 receptor, sigma2R
External IDsOMIM: 612912; MGI: 1916321; HomoloGene: 6443; GeneCards: TMEM97; OMA:TMEM97 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

27346

69071

Ensembl

ENSG00000109084

ENSMUSG00000037278

UniProt

Q5BJF2

Q8VD00

RefSeq (mRNA)

NM_014573

NM_133706

RefSeq (protein)

NP_055388

NP_598467

Location (UCSC)Chr 17: 28.32 – 28.33 MbChr 11: 78.43 – 78.44 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The sigma-2 receptor (σ2R) is a sigma receptor subtype that has attracted attention due to its involvement in diseases such as neurological diseases, neurodegenerative, neuro-ophthalmic and cancer. It is currently [when?] under investigation for its potential diagnostic and therapeutic uses.[5]

Although the sigma-2 receptor was identified as a separate pharmacological entity from the sigma-1 receptor in 1990,[6] the gene that codes for the receptor was identified as TMEM97 only in 2017.[7] TMEM97 was shown to regulate the cholesterol transporter NPC1 and to be involved in cholesterol homeostasis.[8][9] The sigma-2 receptor is a four-pass transmembrane protein located in the endoplasmic reticulum. It has been found to play a role in both hormone signaling and calcium signaling, in neuronal signaling, in cell proliferation and death, and in binding of antipsychotics.[10]

Classification

The sigma-2 receptor is located in the lipid raft.[11] The sigma-2 receptor is found in several areas of the brain, including high densities in the cerebellum, motor cortex, hippocampus, and substantia nigra.[12] It is also highly expressed in the lungs, liver, and kidneys.[10]

Function

The sigma-2 receptor takes part in a number of normal-function roles such as cholesterol homeostasis.[13][14][15]

Non-neuronal signaling

Binding of a number of hormones and steroids, including testosterone, progesterone, and cholesterol, has been found to occur with sigma-2 receptors,[10] though in some cases with lower affinity than to the sigma-1 receptor.[12] Signaling caused by this binding is thought to occur via a calcium secondary messenger[16] and calcium-dependent phosphorylation,[12] and in association with sphingolipids[16] following endoplasmic reticulum release of calcium.[17] Known effects include decrease of expression of effectors in the mTOR pathway, and suppression of cyclin D1 and PARP-1.[17]

Neuronal signaling

Signaling action in neurons by sigma-2 receptors and their associated ligands results in modulation of action potential firing by regulation of calcium channels and potassium channels.[16] They also are involved in synaptic vesicular release and modulation of dopamine, serotonin, and glutamate,[16] with activation and increase of the dopaminergic, serotonergic, and noradrenergic activity of neurons.[12][18]

Cell proliferation

Sigma-2 receptors have been found to be highly expressed in proliferating cells, including tumor cells,[19] and to play a role in the differentiation, morphology, and survival of those cells.[17] By interacting with EGFR membrane proteins sigma-2 receptors play a role in the regulation of signals further downstream such as PKC and RAF. Both PKC and Raf kinase up regulate transcription and cell proliferation.[17]

Ligands

Ligands of the sigma-2 receptor are exogenous and internalized by endocytosis, and can act as either agonists or antagonists. They can typically be classified into four groups, which are structurally related. It is not entirely understood how binding to the sigma-2 receptor occurs.[17] Proposed models commonly include one small and one bulky hydrophobic pocket, electrostatic hydrogen interactions, and less commonly a third hydrophobic pocket.

Class Name[16] Common compounds[16]
6,7-Dimethoxytetrahydroisoquinoline analogs RHM-4, [18F]ISO-1, [125I]ISO-2
Tropane and granatane analogs BIMU-1, FEM-1689, SW107, SW116, SW120
Indole analogs Siramesine, Ibogaine
Cyclohexylpiperazine analogs PB28, F281

A study of the four groups has revealed that a basic nitrogen and at least one hydrophobic moiety is needed to bind a sigma-2 receptor. In addition, there are molecular characteristics that increase the selectivity for sigma-2 receptors, which include bulky hydrophobic regions, nitrogen-carboxylic interaction, and additional basic nitrogens.[17]

Since its discovery in 1990, the sigma-2 receptor has been considered an orphan receptor; however, in 2021 20S-hydroxycholesterol was identified as the putative endogenous ligand.[20][21]

Another ligand is Lu 29-252.

Diagnostic use

This is a figure shows several different brain imaging scans using [18F]ISO-1 sigma-2 receptor ligands. The scans allow tracking of tumor growth and cancer progression over a 10-week period. The figure also includes MRI scans for comparison with PET scans.

Sigma-2 receptors are highly expressed in breast, ovarian, lung cancers, brain, bladder, colon cancers, and melanoma.[10][19] This novelty makes them a valuable biomarker for identifying cancerous tissues. Furthermore, studies have shown that they are more highly expressed in malignant tumors than dormant tumors.[16]

Exogenous sigma-2 receptor ligands have been altered to be neuronal-tracers, used to map cells and their connections. These tracers have high selectivity and affinity for sigma-2 receptors, and high lipophilicity, making them ideal for usage in the brain.[5] Because sigma-2 receptors are highly expressed in tumor cells and are part of the cell proliferation mechanism, PET scans using sigma-2 targeted tracers can reveal if a tumor is proliferating and what its growth rate is.[5]

Therapeutic use

Neurodegenerative and Neuro-ophthalmic Diseases

The sigma-2 receptor is expressed in brain[22] and retinal cells[23][24] where it regulates key pathways involved in age-related diseases such as Alzheimer's disease and synucleinopathies such as Parkinson's disease and dementia with Lewy bodies,[25] as well as dry age-related macular degeneration (dry AMD). The normal activity of processes regulated by sigma-2, such as protein trafficking and autophagy, is impaired by cellular stresses such as oxidative stress and the build-up of amyloid-β and α-synuclein oligomers.[25] Studies support that sigma-2 modulators can rescue biological processes that are impaired in neurodegenerative diseases.[26][27]

In vitro studies of experimental sigma-2 receptor modulators demonstrated an ability to prevent the binding of amyloid-β oligomers to neurons and also to displace bound amyloid-β oligomers from neuronal receptors.[28] In addition, transgenic mice treated sigma-2 receptor modulators performed significantly better in the Morris water maze task than did vehicle-treated mice.[28] Taken together, these studies suggest that sigma-2 receptor modulation may be a viable approach for treating certain neurodegenerative diseases of the CNS and retina.

Neuropsychiatric

Due to the binding capabilities of antipsychotic drugs[10][18] and various neurotransmitters associated with mood,[16] the sigma-2 receptor is a viable target for therapies related to neuropsychiatric disorders and modulation of emotional response.[12] It is thought to be involved in the pathophysiology of schizophrenia,[29] and sigma-2 receptors have been shown to be less abundant in schizophrenic patients.[18] Additionally, PCP, which is an NMDA antagonist, can induce schizophrenia,[29] while sigma-2 receptor activation has been shown to antagonize effects of PCP, implying antipsychotic capabilities.[18] Sigma receptors are a potential target for treatment of dystonia, given high densities in affected regions of the brain.[29] Anti-ischemics ifenprodil and eliprodil, the binding of which increases blood flow, have also shown affinity to sigma receptors.[29] In experimental trials in mice and rats, the sigma-2 receptor ligand siramesine caused reduced anxiety and displayed antidepressant capabilities,[18] while other studies have shown inhibition of selective sigma receptor radioligands by antidepressants, in the mouse and rat brain.[12]

Cancer

Sigma-2 receptors have been associated with pancreatic cancer, lung cancer, breast cancer, melanoma, prostate cancer, and ovarian cancer. Tumor cells are shown to over-express sigma-2 receptors, allowing for potential cancer therapies as many sigma-2 receptor mediated cell responses happen only in tumor cells.[5] Tumor cell responses are modulated via ligand binding. Sigma receptor ligands can act as agonists or antagonists, generating different cellular responses. Agonists inhibit tumor cell proliferation and induce apoptosis, which is thought to be triggered by caspase-3 activity. Antagonists promote tumor cell proliferation, but this mechanism is less understood.[17] Sigma receptor ligands have been conjugated to nanoparticles and peptides to deliver cancer treatment to tumor cells without targeting other tissues.[5] The success with these methods have been limited to in vitro trials. Additionally, using sigma-2 receptors to target tumor cells allows for synergizing anti-cancer drug therapies. Some studies have shown that certain sigma receptor inhibitors increase cancer cells' susceptibility to chemotherapy.[10] Other types of binding to sigma-2 receptors increases cytotoxicity of doxorubicin, antinomyocin, and other cancer cell killing drugs.[17]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000109084 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000037278 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c d e van Waarde A, Rybczynska AA, Ramakrishnan NK, Ishiwata K, Elsinga PH, Dierckx RA (October 2015). "Potential applications for sigma receptor ligands in cancer diagnosis and therapy". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1848 (10 Pt B): 2703–2714. doi:10.1016/j.bbamem.2014.08.022. PMID 25173780.
  6. ^ Hellewell SB, Bowen WD (September 1990). "A sigma-like binding site in rat pheochromocytoma (PC12) cells: decreased affinity for (+)-benzomorphans and lower molecular weight suggest a different sigma receptor form from that of guinea pig brain". Brain Research. 527 (2): 244–253. doi:10.1016/0006-8993(90)91143-5. PMID 2174717. S2CID 24546226.
  7. ^ Alon A, Schmidt HR, Wood MD, Sahn JJ, Martin SF, Kruse AC (July 2017). "Identification of the gene that codes for the σ2 receptor". Proceedings of the National Academy of Sciences of the United States of America. 114 (27). PNAS (Early edition): 7160–7165. Bibcode:2017PNAS..114.7160A. doi:10.1073/pnas.1705154114. PMC 5502638. PMID 28559337.
  8. ^ Bartz F, Kern L, Erz D, Zhu M, Gilbert D, Meinhof T, et al. (July 2009). "Identification of cholesterol-regulating genes by targeted RNAi screening". Cell Metabolism. 10 (1): 63–75. doi:10.1016/j.cmet.2009.05.009. PMID 19583955.
  9. ^ Ebrahimi-Fakhari D, Wahlster L, Bartz F, Werenbeck-Ueding J, Praggastis M, Zhang J, et al. (August 2016). "Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells". Human Molecular Genetics. 25 (16): 3588–3599. doi:10.1093/hmg/ddw204. PMC 5179952. PMID 27378690.
  10. ^ a b c d e f Ahmed IS, Chamberlain C, Craven RJ (March 2012). "S2R(Pgrmc1): the cytochrome-related sigma-2 receptor that regulates lipid and drug metabolism and hormone signaling". Expert Opinion on Drug Metabolism & Toxicology. 8 (3): 361–370. doi:10.1517/17425255.2012.658367. PMID 22292588. S2CID 207491179.
  11. ^ Gebreselassie D, Bowen WD (June 2004). "Sigma-2 receptors are specifically localized to lipid rafts in rat liver membranes". European Journal of Pharmacology. 493 (1–3): 19–28. doi:10.1016/j.ejphar.2004.04.005. PMID 15189760.
  12. ^ a b c d e f Skuza G (November 2003). "Potential antidepressant activity of sigma ligands" (PDF). Polish Journal of Pharmacology. 55 (6): 923–934. PMID 14730086.
  13. ^ Riad A, Zeng C, Weng CC, Winters H, Xu K, Makvandi M, et al. (November 2018). "Sigma-2 Receptor/TMEM97 and PGRMC-1 Increase the Rate of Internalization of LDL by LDL Receptor through the Formation of a Ternary Complex". Scientific Reports. 8 (1): 16845. Bibcode:2018NatSR...816845R. doi:10.1038/s41598-018-35430-3. PMC 6238005. PMID 30443021.
  14. ^ Ebrahimi-Fakhari D, Wahlster L, Bartz F, Werenbeck-Ueding J, Praggastis M, Zhang J, et al. (August 2016). "Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells". Human Molecular Genetics. 25 (16): 3588–3599. doi:10.1093/hmg/ddw204. PMC 5179952. PMID 27378690.
  15. ^ Bartz F, Kern L, Erz D, Zhu M, Gilbert D, Meinhof T, et al. (July 2009). "Identification of cholesterol-regulating genes by targeted RNAi screening". Cell Metabolism. 10 (1): 63–75. doi:10.1016/j.cmet.2009.05.009. PMID 19583955.
  16. ^ a b c d e f g h Narayanan S, Bhat R, Mesangeau C, Poupaert JH, McCurdy CR (January 2011). "Early development of sigma-receptor ligands". Future Medicinal Chemistry. 3 (1): 79–94. doi:10.4155/fmc.10.279. PMID 21428827.
  17. ^ a b c d e f g h Huang YS, Lu HL, Zhang LJ, Wu Z (May 2014). "Sigma-2 receptor ligands and their perspectives in cancer diagnosis and therapy". Medicinal Research Reviews. 34 (3): 532–566. doi:10.1002/med.21297. PMID 23922215. S2CID 25398345.
  18. ^ a b c d e Skuza G (2012). "Pharmacology of sigma (σ) receptor ligands from a behavioral perspective". Current Pharmaceutical Design. 18 (7): 863–874. doi:10.2174/138161212799436458. PMID 22288408.
  19. ^ a b Damaskos C, Garmpis N, Karatzas T, Kostakis ID, Nikolidakis L, Kostakis A, et al. (December 2014). "Nuclear receptors in pancreatic tumor cells". Anticancer Research. 34 (12): 6897–6911. PMID 25503115.
  20. ^ Lowe D (November 22, 2021). "Another Orphan Reunited". In The Pipeline. Science.
  21. ^ Cheng YS, Zhang T, Ma X, Pratuangtham S, Zhang GC, Ondrus AA, et al. (December 2021). "A proteome-wide map of 20(S)-hydroxycholesterol interactors in cell membranes". Nature Chemical Biology. 17 (12): 1271–1280. doi:10.1038/s41589-021-00907-2. PMC 8607797. PMID 34799735.
  22. ^ Karlsson M, Zhang C, Méar L, Zhong W, Digre A, Katona B, et al. (July 2021). "A single-cell type transcriptomics map of human tissues". Science Advances. 7 (31). Bibcode:2021SciA....7.2169K. doi:10.1126/sciadv.abh2169. PMC 8318366. PMID 34321199.
  23. ^ Ratnapriya R, Sosina OA, Starostik MR, Kwicklis M, Kapphahn RJ, Fritsche LG, et al. (April 2019). "Retinal transcriptome and eQTL analyses identify genes associated with age-related macular degeneration". Nature Genetics. 51 (4): 606–610. doi:10.1038/s41588-019-0351-9. PMC 6441365. PMID 30742112.
  24. ^ Wang H, Peng Z, Li Y, Sahn JJ, Hodges TR, Chou TH, et al. (December 2022). "σ2R/TMEM97 in retinal ganglion cell degeneration". Scientific Reports. 12 (1): 20753. Bibcode:2022NatSR..1220753W. doi:10.1038/s41598-022-24537-3. PMC 9715665. PMID 36456686.
  25. ^ a b Limegrover CS, Yurko R, Izzo NJ, LaBarbera KM, Rehak C, Look G, et al. (April 2021). "Sigma-2 receptor antagonists rescue neuronal dysfunction induced by Parkinson's patient brain-derived α-synuclein". Journal of Neuroscience Research. 99 (4): 1161–1176. doi:10.1002/jnr.24782. PMC 7986605. PMID 33480104.
  26. ^ Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F, et al. (12 November 2014). "Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits". PLOS ONE. 9 (11): e111898. Bibcode:2014PLoSO...9k1898I. doi:10.1371/journal.pone.0111898. PMC 4229098. PMID 25390368.
  27. ^ Izzo NJ, Xu J, Zeng C, Kirk MJ, Mozzoni K, Silky C, et al. (12 November 2014). "Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity". PLOS ONE. 9 (11): e111899. Bibcode:2014PLoSO...9k1899I. doi:10.1371/journal.pone.0111899. PMC 4229119. PMID 25390692.
  28. ^ a b Izzo NJ, Yuede CM, LaBarbera KM, Limegrover CS, Rehak C, Yurko R, et al. (August 2021). "Preclinical and clinical biomarker studies of CT1812: A novel approach to Alzheimer's disease modification". Alzheimer's & Dementia. 17 (8): 1365–1382. doi:10.1002/alz.12302. PMC 8349378. PMID 33559354.
  29. ^ a b c d Hashimoto K, Ishiwata K (1 October 2006). "Sigma receptor ligands: possible application as therapeutic drugs and as radiopharmaceuticals". Current Pharmaceutical Design. 12 (30): 3857–3876. doi:10.2174/138161206778559614. PMID 17073684.

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