The sigma-2 receptor (σ
2R) is a
sigma receptor
Sigma receptors (σ-receptors) are protein cell surface receptors that bind ligands such as 4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine), SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. There are two subtypes, ...
subtype that has attracted attention due to its involvement in diseases such as
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
and
neurological diseases
A neurological disorder is any disorder of the nervous system. Structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves can result in a range of symptoms. Examples of symptoms include paralysis, muscle weakne ...
. It is currently 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
The sigma-1 receptor (σ1R), one of two sigma receptor subtypes, is a chaperone protein at the endoplasmic reticulum (ER) that modulates calcium signaling through the IP3 receptor. In humans, the σ1 receptor is encoded by the ''SIGMAR1'' gene ...
in 1990, the gene that codes for the receptor was identified as TMEM97 only in 2017. TMEM97 was shown to regulate the
cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell membr ...
transporter
NPC1
Niemann-Pick disease, type C1 (NPC1) is a disease of a membrane protein that mediates intracellular cholesterol trafficking in mammals. In humans the protein is encoded by the ''NPC1'' gene (chromosome location 18q11).
Function
NPC1 was identi ...
and to be involved in cholesterol
homeostasis
In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
. The sigma-2 receptor is a four-pass transmembrane protein located in the
endoplasmic reticulum
The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough 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.
Classification
The sigma-2 receptor is located in the
lipid raft
The cell membrane, plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein Receptor (biochemistry), receptors organised in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular mem ...
.
The sigma-2 receptor is found in several areas of the brain, including high densities in the
cerebellum
The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cere ...
,
motor cortex
The motor cortex is the region of the cerebral cortex believed to be involved in the planning, control, and execution of voluntary movements.
The motor cortex is an area of the frontal lobe located in the posterior precentral gyrus immediately ...
,
hippocampus
The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...
, and
substantia nigra
The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra a ...
.
It is also highly expressed in the
lungs
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of ...
,
liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
, and
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; bloo ...
s.
Function
The sigma-2 receptor takes part in a number of normal-function roles, including cell
proliferation
Proliferation may refer to:
Weapons
*Nuclear proliferation, the spread of nuclear weapons, material, and technology
*Chemical weapon proliferation, the spread of chemical weapons, material, and technology
* Small arms proliferation, the spread of ...
, non-neuronal, and neuronal signaling. Much of sigma-2 receptor function relies on signaling cascades. The receptor's interaction with EGFR and PGRMC1 proteins allow for sigma-2 receptors to play diverse roles within cell through
Ras,
PLC, and
PI3K
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
singaling.
Non-neuronal signaling
Binding of a number of
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
s and
steroid
A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...
s, including
testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteris ...
,
progesterone
Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
, and
cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell membr ...
, has been found to occur with sigma-2 receptors,
though in some cases with lower
affinity than to the
sigma-1 receptor
The sigma-1 receptor (σ1R), one of two sigma receptor subtypes, is a chaperone protein at the endoplasmic reticulum (ER) that modulates calcium signaling through the IP3 receptor. In humans, the σ1 receptor is encoded by the ''SIGMAR1'' gene ...
.
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
The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...
release of
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...
.
Known effects include decrease of expression of effectors in the mTOR pathway, and suppression of cyclin D1 and PARP-1.
Neuronal signaling
Signaling action in
neuron
A neuron, neurone, or nerve cell is an membrane potential#Cell excitability, electrically excitable cell (biology), cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous ...
s by sigma-2 receptors and their associated
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ele ...
s results in modulation of
action potential
An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...
firing by regulation of calcium and potassium channels.
They also are involved in synaptic vesicular release and modulation of
dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 8 ...
,
serotonin, and
glutamate
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
,
with activation and increase of the
dopaminergic
Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate do ...
,
serotonergic
Serotonergic () or serotoninergic () means "pertaining to or affecting serotonin". Serotonin is a neurotransmitter. A synapse
In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chem ...
, and
noradrenergic activity of neurons.
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
In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It contrasts with endogeneity or endogeny, the fact of being influenced within a system.
Economics
In an economic model, an exogen ...
and internalized by
endocytosis
Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. E ...
, and can act as either
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
s 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
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, ...
pocket,
electrostatic
Electrostatics is a branch of physics that studies electric charges at rest (static electricity).
Since classical times, it has been known that some materials, such as amber, attract lightweight particles after rubbing. The Greek word for am ...
hydrogen interactions, and less commonly a third hydrophobic pocket.
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.
Since its discovery in 1990, the sigma-2 receptor has been considered an
orphan receptor
In biochemistry, an orphan receptor is a protein that has a similar structure to other identified receptors but whose endogenous ligand has not yet been identified. If a ligand for an orphan receptor is later discovered, the receptor is referred t ...
; however, in 2021
20S-hydroxycholesterol
20S-Hydroxycholesterol is a steroid of the oxysterol class. It is a human metabolite of cholesterol.
20S-Hydroxycholesterol has been the subject of research into its role in human health. For example, 20S-hydroxycholesterol has been found to ...
was identified as the putative
endogenous ligand.
Diagnostic use

Sigma-2 receptors are highly expressed breast, ovarian, lung cancers, brain, bladder, colon cancers, and
melanoma.
This novelty makes them a valuable
biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...
for identifying cancerous tissues. Furthermore, studies have shown that they are more highly expressed in
malignant tumor
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal ble ...
s than dormant tumors.
Exogenous
In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It contrasts with endogeneity or endogeny, the fact of being influenced within a system.
Economics
In an economic model, an exogen ...
sigma-2 receptor
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ele ...
s 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
Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipo ...
, 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 scan
Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, r ...
s using sigma-2 targeted tracers can reveal if a tumor is proliferating and what its growth rate is.
Therapeutic use
Neuropsychiatric
Due to the binding capabilities of
antipsychotic
Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range o ...
drugs
and various
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neur ...
s associated with mood,
the sigma-2 receptor is a viable target for therapies related to
neuropsychiatric disorders and modulation of emotional response.
It is thought to be involved in the
pathophysiology
Pathophysiology ( physiopathology) – a convergence of pathology with physiology – is the study of the disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is t ...
of
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wi ...
,
and sigma-2 receptors have been shown to be less abundant in schizophrenic patients.
Additionally, PCP, which is an NMDA antagonist, can induce
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wi ...
,
while sigma-2 receptor activation has been shown to antagonize effects of
PCP, implying
antipsychotic
Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range o ...
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
Siramesine (or Lu 28-179) is a sigma receptor agonist, selective for the σ2 subtype. In animal studies, siramesine has been shown to produce anxiolytic and antidepressant effects. It was developed by the pharmaceutical company H Lundbeck for th ...
caused reduced anxiety and displayed antidepressant capabilities,
while other studies have shown inhibition of selective sigma receptor
radioligand
A radioligand is a radioactive biochemical substance (in particular, a ligand that is radiolabeled) that is used for diagnosis or for research-oriented study of the receptor systems of the body.
In a neuroimaging application the radioligand is ...
s by antidepressants, in the mouse and rat brain.
Cancer
Sigma-2 receptors have been associated with
pancreatic cancer
Pancreatic cancer arises when cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a mass. These cancerous cells have the ability to invade other parts of the body. A number of types of panc ...
,
lung cancer
Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissues of the lung. Lung carcinomas derive from transformed, malign ...
,
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...
,
melanoma,
prostate cancer
Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that su ...
, and
ovarian cancer
Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different ...
.
Tumor
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
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
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
s or
antagonists, generating different cellular responses.
Agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
s
inhibit
Inhibitor or inhibition may refer to:
In biology
* Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity
* Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotr ...
tumor
cell proliferation and induce
apoptosis, which is thought to be triggered by
caspase-3
Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the ''CASP3'' gene. ''CASP3'' orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also ...
activity. Antagonists promote tumor cell proliferation, but this mechanism is less understood.
Sigma receptor ligands have been conjugated to
nanoparticle
A nanoparticle or ultrafine particle is usually defined as a particle of matter that is between 1 and 100 nanometres (nm) in diameter. The term is sometimes used for larger particles, up to 500 nm, or fibers and tubes that are less than 10 ...
s and peptides to deliver cancer treatment to tumor cells without targeting other tissues.
The success with these methods have been limited to
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology and ...
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
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...
.
Other types of binding to sigma-2 receptors increases
cytotoxicity of doxorubicin, antinomyocin, and other cancer cell killing drugs.
See also
*
Sigma-1 receptor
The sigma-1 receptor (σ1R), one of two sigma receptor subtypes, is a chaperone protein at the endoplasmic reticulum (ER) that modulates calcium signaling through the IP3 receptor. In humans, the σ1 receptor is encoded by the ''SIGMAR1'' gene ...
*
Sigma receptor
Sigma receptors (σ-receptors) are protein cell surface receptors that bind ligands such as 4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine), SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. There are two subtypes, ...
References
External links
*
{{Sigma receptor modulators
Signal transduction
Cell signaling