Sigma-2 receptor

Binding of a number of hormones and steroids, including testosterone, progesterone, and cholesterol, has been found to occur with sigma-2 receptors,[7] though in some cases with lower affinity than to the sigma-1 receptor.[9] Signaling caused by this binding is thought to occur via a calcium secondary messenger[10] and calcium-dependent phosphorylation,[9] and in association with sphingolipids[10] following endoplasmic reticulum release of calcium.[11] Known effects include decrease of expression of effectors in the mTOR pathway, and suppression of cyclin D1 and PARP-1.[11]

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.[10] They also are involved in synaptic vesicular release and modulation of dopamine, serotonin, and glutamate,[10] with activation and increase of the dopaminergic, serotonergic, and noradrenergic activity of neurons.[9][12]

Sigma-2 receptors have been found to be highly expressed in proliferating cells, including tumor cells,[13] and to play a role in the differentiation, morphology, and survival of those cells.[11] 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.[11]

Due to the binding capabilities of antipsychotic drugs[7][12] and various neurotransmitters associated with mood,[10] the sigma-2 receptor is a viable target for therapies related to neuropsychiatric disorders and modulation of emotional response.[9] It is thought to be involved in the pathophysiology of schizophrenia,[14] and sigma-2 receptors have been shown to be less abundant in schizophrenic patients.[12] Additionally, PCP, which is an NMDA antagonist, can induce schizophrenia,[14] while sigma-2 receptor activation has been shown to antagonize effects of PCP, implying antipsychotic capabilities.[12] Sigma receptors are a potential target for treatment of dystonia, given high densities in affected regions of the brain.[14] Anti-ischemics ifenprodil and eliprodil, the binding of which increases blood flow, have also shown affinity to sigma receptors.[14] In experimental trials in mice and rats, the sigma-2 receptor ligand siramesine caused reduced anxiety and displayed antidepressant capabilities,[12] while other studies have shown inhibition of selective sigma receptor radioligands by antidepressants, in the mouse and rat brain.[9]

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.[11] 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.[7] Other types of binding to sigma-2 receptors increases cytotoxicity of doxorubicin, antinomyocin, and other cancer cell killing drugs.[11]