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Sigma-2 receptor
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.
Although the sigma-2 receptor was identified as a separate pharmacological entity from the sigma-1 receptor in 1990, the gene that codes for the receptor was identified as TMEM97 only in 2017. 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.
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.
The sigma-2 receptor takes part in a number of normal-function roles such as cholesterol homeostasis.
Binding of a number of hormones and steroids, including testosterone, progesterone, and cholesterol, has been found to occur with sigma-2 receptors, though in some cases with lower affinity than to the sigma-1 receptor. Signaling caused by this binding is thought to occur via a calcium secondary messenger and calcium-dependent phosphorylation, and in association with sphingolipids following endoplasmic reticulum release of calcium. Known effects include decrease of expression of effectors in the mTOR pathway, and suppression of cyclin D1 and PARP-1.
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. They also are involved in synaptic vesicular release and modulation of dopamine, serotonin, and glutamate, with activation and increase of the dopaminergic, serotonergic, and noradrenergic activity of neurons.
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 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. Proposed models commonly include one small and one bulky hydrophobic pocket, electrostatic hydrogen interactions, and less commonly a third hydrophobic pocket.
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Sigma-2 receptor
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.
Although the sigma-2 receptor was identified as a separate pharmacological entity from the sigma-1 receptor in 1990, the gene that codes for the receptor was identified as TMEM97 only in 2017. 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.
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.
The sigma-2 receptor takes part in a number of normal-function roles such as cholesterol homeostasis.
Binding of a number of hormones and steroids, including testosterone, progesterone, and cholesterol, has been found to occur with sigma-2 receptors, though in some cases with lower affinity than to the sigma-1 receptor. Signaling caused by this binding is thought to occur via a calcium secondary messenger and calcium-dependent phosphorylation, and in association with sphingolipids following endoplasmic reticulum release of calcium. Known effects include decrease of expression of effectors in the mTOR pathway, and suppression of cyclin D1 and PARP-1.
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. They also are involved in synaptic vesicular release and modulation of dopamine, serotonin, and glutamate, with activation and increase of the dopaminergic, serotonergic, and noradrenergic activity of neurons.
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 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. Proposed models commonly include one small and one bulky hydrophobic pocket, electrostatic hydrogen interactions, and less commonly a third hydrophobic pocket.