Sigma-2 receptor

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

The sigma-2 receptor takes part in a number of normal-function roles such as cholesterol homeostasis. 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, following endoplasmic reticulum release of calcium. 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. Cell proliferation Sigma-2 receptors have been found to be highly expressed in proliferating cells, including tumor cells, and to play a role in the differentiation, morphology, and survival of those cells. 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. == 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. Another ligand is Lu 29-252. == Diagnostic use ==

File:PET scans of brain tumor using Sigma-2 Ligands.png|thumb|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. 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. 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. 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. == Therapeutic use ==

Neurodegenerative and Neuro-ophthalmic Diseases The sigma-2 receptor is expressed in brain and retinal cells 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, 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. 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. In addition, transgenic mice treated sigma-2 receptor modulators performed significantly better in the Morris water maze task than did vehicle-treated mice. and sigma-2 receptors have been shown to be less abundant in schizophrenic patients. Additionally, PCP, which is an NMDA antagonist, can induce schizophrenia, while sigma-2 receptor activation has been shown to antagonize effects of PCP, implying antipsychotic capabilities. Sigma receptors are a potential target for treatment of dystonia, given high densities in affected regions of the brain. Anti-ischemics ifenprodil and eliprodil, the binding of which increases blood flow, have also shown affinity to sigma receptors. In experimental trials in mice and rats, the sigma-2 receptor ligand siramesine caused reduced anxiety and displayed antidepressant capabilities, while other studies have shown inhibition of selective sigma receptor radioligands by antidepressants, in the mouse and rat brain. 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. 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. Sigma receptor ligands have been conjugated to nanoparticles and peptides to deliver cancer treatment to tumor cells without targeting other tissues. 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. Other types of binding to sigma-2 receptors increases cytotoxicity of doxorubicin, antinomyocin, and other cancer cell killing drugs. == See also ==