The sigma-2 receptor (σ2R) is a sigma receptor subtype which has been found highly expressed in malignant cancer cells, and is currently under investigation for its potential diagnostic and therapeutic uses.[1] Originally, it was thought that the sigma receptors were a type of opiate receptor, due to its ability to bind ligands such as benzomorphans and PCP.[2] Certain ligands presented similar affinities to both the sigma receptor, and the PCP receptor, making it hard to distinguish between the two. With the use of more selective ligands, scientists were able to determine that the two receptors were different, and had different distributions throughout the brain.[2] The sigma-2 receptor in particular is more densely located in parts of the brain that are responsible for motor function and emotional response. It has been found to play a role in both hormone signaling and calcium signaling, in cell proliferation and death, and in binding of antipsychotics.[3] Still, the position of the sigma-2 receptor has not yet been officially located on the human chromosome, and its existence has only been established pharmacologically (1).
Classification edit
The sigma-2 receptor is a cytochrome related protein[3] located in the lipid raft[4] that is most commonly associated with P450 proteins,[3] and is coupled with the PGRMC1 complex, EGFR, mTOR, caspases, and various ion channels.[5] It was previously thought to be the same as the NMDA receptor, is non-opioid,[4] does not translocate, and unlike the sigma-1 receptor, has not been cloned.[4][2][5] The sigma-2 receptor is found in several areas of the brain, including high densities in the cerebellum, motor cortex, and substantia nigra, though it shows no homology with other proteins present in brain tissue.[2] It is also highly expressed in the lungs, liver, and kidneys.[3]
Function edit
The sigma-2 receptor takes part in a number of normal-function roles, including cell proliferation, and non-neuronal and neuronal signaling.
Non-neuronal signaling edit
Binding of a number of hormones and steroids, including testosterone, progesterone, and cholesterol, has been found to occur with sigma-2 receptors,[3] though in some cases with lower affinity than to the sigma-1 receptor.[2] Signaling caused by this binding is thought to occur via a calcium secondary messenger[4] and calcium-dependent phosphorylation,[2] and in association with sphingolipids[4] following endoplasmic reticulum release of calcium.[5] Known effects include decrease of expression of effectors in the mTOR pathway, and suppression of cyclin D1 and PARP-1.[5]
Neuronal signaling edit
Signaling action in neurons by sigma-2 receptors and their associated ligands results in modulation of action potential firing by regulation of calcium and potassium channels.[4] They also are involved in synaptic vesicular release and modulation of dopamine, serotonin, and glutamate,[4] with activation and increase of the dopaminergic, serotonergic, and noradrenergic activity of neurons.[2][6]
Cell proliferation edit
Sigma-2 receptors have been found to be highly expressed in proliferating cells, including tumor cells,[7] and to play a role in the differentiation, morphology, and survival of those cells.[5]
Ligands edit
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.[5]
| Class Name[4] | Common compounds[4] |
|---|---|
| 6,7-Dimethoxytetrahydroisoquinoline analogs | RHM-4, [18F]ISO-1, [125I]ISO-2 |
| Tropane and granatane analogs | BIMU-1, SW107, SW116, SW120 |
| Indole analogs | Siramesine, Ibogaine |
| Cyclohexylpiperazine analogs | PB28, F281} |
Diagnostic use edit
Sigma-2 receptors are highly expressed breast, ovarian, lung cancers, brain, bladder, colon cancers, and melanoma.[3][7] 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.[4]
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.[1] 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.[1]
Therapeutic use edit
Neuropsychiatric edit
Due to the binding capabilities of antipsychotic drugs[3][6] and various neurotransmitters associated with mood,[4] the sigma-2 receptor is a viable target for therapies related to neuropsychiatric disorders and modulation of emotional response.[2] It is thought to be involved in the pathophysiology of schizophrenia,[8] and sigma-2 receptors have been shown to be less abundant is schizophrenic patients.[6] Additionally, PCP, which is an NMDA antagonist, can induce schizophrenia,[8] while sigma-2 receptor activation has been shown to antagonize effects of PCP, implying antipsychotic capabilities[6]. Sigma receptors are a potential target for treatment of dystonia, given high densities in effected regions of the brain.[8] Anti-ischemics ifenprodil and eliprodil, the binding of which increases blood flow, have also shown affinity to sigma receptors.[8] In experimental trials in mice and rats, the sigma-2 receptor ligand siramensine caused reduced anxiety and antidepressant capabilities,[6] while other studies have shown inhibition of selective sigma receptor radioligands by antidepressants, in the mouse and rat brain.[2]
Cancer edit
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.[1] 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.[5] Sigma receptor ligands have been conjugated to nanoparticles and peptides to deliver cancer treatment to tumor cells without targeting other tissues.[1] 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.[3] Other types of binding to sigma-2 receptors increases cytotoxicity of doxorubicin, antinomyocin, and other cancer cell killing drugs.[5]
References edit
- ^ a b c d e van Waarde, A; Rybczynska, AA; et al. (August 27, 2014). "Potential applications for sigma receptor ligands in cancer diagnosis and therapy". Biochimica et Biophysica Acta- Biomembranes. doi:10.1016/j.bbamem.2014.08.022. PMID 25173780.
{{cite journal}}: Explicit use of et al. in:|last3=(help) - ^ a b c d e f g h i Skuza, G (November 2003). "Potential antidepressant activity of sigma ligands" (PDF). Polish Journal of Pharmacology. 55 (6): 923–934. ISSN 1230-6002. PMID 14730086.
- ^ a b c d e f g h Ahmed, IS; Chamberlin, 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. PMID 22292588.
- ^ a b c d e f g h i j k Narayanan, S; Rohit, Bhat; et al. (January 2011). "Early development of sigma-receptor ligands". Future Medicinal Chemistry. 3 (1): 79–94. doi:10.4155/fmc.10.279. PMID 21428827.
{{cite journal}}: Explicit use of et al. in:|last3=(help) - ^ a b c d e f g h Huang, Y; Lu, H; et al. (August 6, 2013). "Sigma-2 Receptor Ligands and Their Perspectives in Cancer Diagnosis and Therapy". Medical Research Reviews. 34 (3): 532–566. doi:10.1002/med.21297. PMID 23922215.
{{cite journal}}: Explicit use of et al. in:|last3=(help) - ^ a b c d e Skuza, G (2012). "Pharmacology of Sigma Receptor Ligand from a Behavioral Perspective". Current Pharmaceutical Design. 18 (7): 863–874. doi:10.2174/138161212799436458. PMID 22288408.
- ^ a b Damaskos, C; Karatzas, T; et al. (December 2014). "Nuclear Receptors in Pancreatic Tumor Cells". Anticancer Research. 34 (12): 6897–6912. PMID 25503115.
{{cite journal}}: Explicit use of et al. in:|last3=(help) - ^ a b c d Hashimoto, 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. PMID 17073684.