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. 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.[8]
The sigma-2 receptor takes part in a number of normal-function roles, including cell proliferation, autophagy,[11] cholesterol homeostasis,[12] and both non-neuronal and neuronal signaling. Much of sigma-2 receptor function relies on signaling cascades. The receptor's interaction with EGFR and PGRMC1 proteins allow for sigma-2 receptors to play diverse roles within cell through Ras, PLC, and PI3K signaling.
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,[8] though in some cases with lower affinity than to the sigma-1 receptor.[10] Signaling caused by this binding is thought to occur via a calcium secondary messenger[13] and calcium-dependent phosphorylation,[10] and in association with sphingolipids[13] following endoplasmic reticulum release of calcium.[14] Known effects include decrease of expression of effectors in the mTOR pathway, and suppression of cyclin D1 and PARP-1.[14]
Sigma-2 receptors have been found to be highly expressed in proliferating cells, including tumor cells,[16] and to play a role in the differentiation, morphology, and survival of those cells.[14] 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.[14]
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.[14] Proposed models commonly include one small and one bulky hydrophobic pocket, electrostatic hydrogen interactions, and less commonly a third hydrophobic pocket.
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.[14]
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.[8][16] 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.[13]
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[19] and retinal cells[20] where it regulates key pathways involved in age-related diseases such as Alzheimer's disease[21] and synucleinopathies such as Parkinson's disease and dementia with Lewy bodies,[22] as well as dry age-related macular degeneration (dry AMD).[23] 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-synucleinoligomers.[24] Studies support that sigma-2 modulators can rescue biological processes that are impaired in neurodegenerative diseases.[25]
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.[26] In addition, transgenic mice treated sigma-2 receptor modulators performed significantly better in the Morris water maze task than did vehicle-treated mice.[27] 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[8][15] and various neurotransmitters associated with mood,[13] the sigma-2 receptor is a viable target for therapies related to neuropsychiatric disorders and modulation of emotional response.[10] It is thought to be involved in the pathophysiology of schizophrenia,[28] and sigma-2 receptors have been shown to be less abundant in schizophrenic patients.[15] Additionally, PCP, which is an NMDA antagonist, can induce schizophrenia,[28] while sigma-2 receptor activation has been shown to antagonize effects of PCP, implying antipsychotic capabilities.[15] Sigma receptors are a potential target for treatment of dystonia, given high densities in affected regions of the brain.[28] Anti-ischemics ifenprodil and eliprodil, the binding of which increases blood flow, have also shown affinity to sigma receptors.[28]
In experimental trials in mice and rats, the sigma-2 receptor ligand siramesine caused reduced anxiety and displayed antidepressant capabilities,[15] while other studies have shown inhibition of selective sigma receptor radioligands by antidepressants, in the mouse and rat brain.[10]
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. Agonistsinhibit 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.[14] 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.[8] Other types of binding to sigma-2 receptors increases cytotoxicity of doxorubicin, antinomyocin, and other cancer cell killing drugs.[14]
^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): 244–53. doi:10.1016/0006-8993(90)91143-5. PMID2174717. S2CID24546226.
^ abcdefAhmed IS, Chamberlain C, Craven RJ (March 2012). "S2RPgrmc1: 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. PMID22292588. S2CID207491179.
^ abcdefghHuang 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. PMID23922215. S2CID25398345.
^ abcdeSkuza G (2012). "Pharmacology of sigma (σ) receptor ligands from a behavioral perspective". Current Pharmaceutical Design. 18 (7): 863–874. doi:10.2174/138161212799436458. PMID22288408.
^ abDamaskos C, Karatzas T, Kostakis ID, Nikolidakis L, Kostakis A, Kouraklis G (Dec 2014). "Nuclear receptors in pancreatic tumor cells". Anticancer Research. 34 (12): 6897–6912. PMID25503115.
^ abcdHashimoto K, Ishiwata K (2006). "Sigma receptor ligands: possible application as therapeutic drugs and as radiopharmaceuticals". Current Pharmaceutical Design. 12 (30): 3857–3876. doi:10.2174/138161206778559614. PMID17073684.
