| TMEM97 | |||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
 | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | TMEM97, MAC30, transmembrane protein 97, Sigma-2 receptor, sigma2R | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM:612912;MGI:1916321;HomoloGene:6443;GeneCards:TMEM97;OMA:TMEM97 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
Thesigma-2 receptor (σ2R) is asigma receptor subtype that has attracted attention due to its involvement in diseases such asneurological diseases,neurodegenerative, neuro-ophthalmic andcancer. It is currently[when?] under investigation for its potential diagnostic and therapeutic uses.[5]
Although the sigma-2 receptor was identified as a separate pharmacological entity from thesigma-1 receptor in 1990,[6] the gene that codes for the receptor was identified asTMEM97 only in 2017.[7]TMEM97 was shown to regulate thecholesterol transporterNPC1 and to be involved in cholesterolhomeostasis.[8][9] The sigma-2 receptor is a four-pass transmembrane protein located in theendoplasmic 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.[10]
The sigma-2 receptor is located in thelipid raft.[11] The sigma-2 receptor is found in several areas of the brain, including high densities in thecerebellum,motor cortex,hippocampus, andsubstantia nigra.[12] It is also highly expressed in thelungs,liver, andkidneys.[10]
The sigma-2 receptor takes part in a number of normal-function roles such as cholesterol homeostasis.[13][14][15]
Binding of a number ofhormones andsteroids, includingtestosterone,progesterone, andcholesterol, has been found to occur with sigma-2 receptors,[10] though in some cases with loweraffinity than to thesigma-1 receptor.[12] Signaling caused by this binding is thought to occur via a calcium secondary messenger[16] and calcium-dependent phosphorylation,[12] and in association withsphingolipids[16] followingendoplasmic reticulum release ofcalcium.[17] Known effects include decrease of expression of effectors in themTOR pathway, and suppression ofcyclin D1 andPARP-1.[17]
Signaling action inneurons by sigma-2 receptors and their associatedligands results in modulation ofaction potential firing by regulation ofcalcium channels andpotassium channels.[16] They also are involved in synaptic vesicular release and modulation ofdopamine,serotonin, andglutamate,[16] with activation and increase of thedopaminergic,serotonergic, andnoradrenergic activity of neurons.[12][18]
Sigma-2 receptors have been found to be highly expressed in proliferating cells, includingtumor cells,[19] and to play a role in the differentiation, morphology, and survival of those cells.[17] By interacting with EGFR membrane proteins sigma-2 receptors play a role in the regulation of signals further downstream such as PKC and RAF. BothPKC andRaf kinase up regulate transcription and cell proliferation.[17]
Ligands of the sigma-2 receptor areexogenous and internalized byendocytosis, and can act as eitheragonists orantagonists. 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.[17] Proposed models commonly include one small and one bulkyhydrophobic pocket,electrostatic hydrogen interactions, and less commonly a third hydrophobic pocket.
| Class Name[16] | Common compounds[16] |
|---|---|
| 6,7-Dimethoxytetrahydroisoquinoline analogs | RHM-4, [18F]ISO-1, [125I]ISO-2 |
| Tropane and granatane analogs | BIMU-1,FEM-1689, SW107, SW116, SW120 |
| Indole analogs | Siramesine,Ibogaine |
| Cyclohexylpiperazine analogs | PB28, F281 |
A study of the four groups has revealed that a basic nitrogen and at least one hydrophobic moiety is needed to bind a sigma-2 receptor. In addition, there are molecular characteristics that increase the selectivity for sigma-2 receptors, which include bulky hydrophobic regions, nitrogen-carboxylic interaction, and additional basic nitrogens.[17]
Since its discovery in 1990, the sigma-2 receptor has been considered anorphan receptor; however, in 202120S-hydroxycholesterol was identified as the putativeendogenous ligand.[20][21]
Another ligand isLu 29-252.
Sigma-2 receptors are highly expressed in breast, ovarian, lung cancers, brain, bladder, colon cancers, andmelanoma.[10][19] This novelty makes them a valuablebiomarker for identifying cancerous tissues. Furthermore, studies have shown that they are more highly expressed inmalignant tumors than dormant tumors.[16]
Exogenous sigma-2 receptorligands have been altered to be neuronal-tracers, used to map cells and their connections. These tracers have highselectivity andaffinity for sigma-2 receptors, and highlipophilicity, making them ideal for usage in the brain.[5] 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.[5]
The sigma-2 receptor is expressed inbrain[22] andretinal cells[23][24] where it regulates key pathways involved in age-related diseases such asAlzheimer's disease and synucleinopathies such asParkinson's disease anddementia with Lewy bodies,[25] as well as dry age-related macular degeneration (dry AMD). The normal activity of processes regulated by sigma-2, such as protein trafficking andautophagy, is impaired by cellular stresses such asoxidative stress and the build-up ofamyloid-β andα-synucleinoligomers.[25] Studies support that sigma-2 modulators can rescue biological processes that are impaired in neurodegenerative diseases.[26][27]
In vitro studies of experimental sigma-2 receptor modulators demonstrated an ability to prevent the binding ofamyloid-β oligomers to neurons and also to displace boundamyloid-β oligomers from neuronal receptors.[28] In addition, transgenic mice treated sigma-2 receptor modulators performed significantly better in the Morris water maze task than did vehicle-treated mice.[28] Taken together, these studies suggest that sigma-2 receptor modulation may be a viable approach for treating certainneurodegenerative diseases of theCNS andretina.
Due to the binding capabilities ofantipsychotic drugs[10][18] and variousneurotransmitters associated with mood,[16] the sigma-2 receptor is a viable target for therapies related toneuropsychiatric disorders and modulation of emotional response.[12] It is thought to be involved in thepathophysiology ofschizophrenia,[29] and sigma-2 receptors have been shown to be less abundant in schizophrenic patients.[18] Additionally, PCP, which is anNMDA antagonist, can induceschizophrenia,[29] while sigma-2 receptor activation has been shown to antagonize effects ofPCP, implyingantipsychotic capabilities.[18] Sigma receptors are a potential target for treatment ofdystonia, given high densities in affected regions of the brain.[29] Anti-ischemicsifenprodil andeliprodil, the binding of which increases blood flow, have also shown affinity to sigma receptors.[29]In experimental trials in mice and rats, the sigma-2 receptor ligandsiramesine caused reduced anxiety and displayed antidepressant capabilities,[18] while other studies have shown inhibition of selective sigma receptorradioligands by antidepressants, in the mouse and rat brain.[12]
Sigma-2 receptors have been associated withpancreatic cancer,lung cancer,breast cancer,melanoma,prostate cancer, andovarian 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 vialigand binding. Sigma receptor ligands can act asagonists orantagonists, generating different cellular responses.Agonistsinhibit tumorcell proliferation and induceapoptosis, which is thought to be triggered bycaspase-3 activity. Antagonists promote tumor cell proliferation, but this mechanism is less understood.[17] Sigma receptor ligands have been conjugated tonanoparticles and peptides to deliver cancer treatment to tumor cells without targeting other tissues.[5] The success with these methods have been limited toin 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 tochemotherapy.[10] Other types of binding to sigma-2 receptors increasescytotoxicity of doxorubicin, antinomyocin, and other cancer cell killing drugs.[17]
