User:Medstudentleigh/Sigma-2 Receptor
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
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
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
Binding of a number of hormones and steroids, including
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 and potassium channels.
Cell proliferation
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
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
Sigma-2 receptors are highly expressed breast, ovarian, lung cancers, brain, bladder, colon cancers, and melanoma.
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.
Therapeutic use
Neuropsychiatric
Due to the binding capabilities of
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.