Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Sigma Receptor (σR)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101870


Historical Background

Sigma receptors [σRs] are a relatively novel group of receptors originally discovered in the central nervous system [CNS] of mammals in 1976. They represent a ubiquitously expressed unique binding site in the CNS and other peripheral tissues. σRs are a member of the orphan receptor class for which no endogenous ligand was known until recently – dimethyltryptamine [DMT] (Fontanilla et al. 2009). They also bind with high affinity to several classes of chemically unrelated ligands such as neurosteroids, neuroleptics, dextrobenzomorphans, and several psychostimulants such as cocaine, methamphetamine, methylenedioxymethamphetamine, and methacathinone. Consequently, it is thought that the σR may mediate the immunosuppressant, antipsychotic, and neuroprotective effects of many drugs (Niitsu et al. 2012).

Historically, the σR was identified as one of the subtypes of opiate receptors, differentiated using a chronic spinal pain model in the dog, the unique psychomimetic effects induced by N-allylnormetazocine [SKF-10,047] (σ-syndrome), from the effects induced by morphine (μ-syndrome) and ketocyclazocine (κ-syndrome). However, subsequent studies established that σR sites possess negligible affinity for naloxone or naltrexone; thus, establishing a complete distinction between the nonopiate σ-binding sites and the classical μ-, δ-, and μ-opiate receptors.

Due to their CNS pharmacological action, most work has been focused on evaluation of σRs in the CNS; however, considerable current research has also been directed toward neoplasia, its treatment and imaging (σ2R). σRs are highly expressed in all parts of the brain, where they are predominantly localized in the cell plasma membrane and at the endoplasmic reticulum [ER] of both neurons and oligodendrocytes (Rousseaux and Greene 2015).

Sigma-1 Receptors [σ1Rs]

The σ1R is a 29-kDa single polypeptide that has been cloned in mice, rats, and humans; the ligand-binding profile of which is similar to those described in brain homogenates studies. The σ1R gene, located on chromosome 9, band p13, in human and chromosome 2 in rodents, is approximately 7 kbp long and contains four exons, interrupted by three introns, where exon 3 is the shortest (93 bp) and exon 4 is the longest (1132 bp). Exon 2 encodes 25 kDa membrane proteins for the single transmembrane domain, identified at present, but two other hydrophobic regions exist and one of them may putatively constitute a second transmembrane domain.

The σ1R sequence contains a 22 amino acid retention signal for the ER at its N-terminal region and two short C-terminal hydrophobic amino acid sequences that are probably involved in sterol binding. The 223 amino acid sequence of the purified protein is highly preserved, with 87–92% identity and 90–93% homology among tissues and animal species. This protein is identical in peripheral tissues and brain, and probably is similar in other tissues as well. It shares a similarity, 33% identity and 66% homology, with a sterol C8–C7 isomerase, but nevertheless is different from any other mammalian protein identified, outlining the uniqueness of the σ1R as compared with any other known receptor.

The σ1R gene also has been isolated from human, guinea pig, mouse, and rat. Amino acid substitutions in transmembrane domains do not alter the expression levels of the protein but suppresses ligand-binding activity, suggesting that these amino acids belong to the binding site pharmacophore located within the transmembrane domain. Exon-2 codes for a single transmembrane domain present in the σR. The fact that the gene for the σ1R is located on chromosome 9p13, a region associated with psychiatric disorders, helps explain the psychiatric effects of σ1R agonists and antagonists.

Sigma-2 Receptors [σ2Rs]

The σ2R site has not been cloned as of yet, but a comprehensive ligand-based mapping of the receptor-binding pocket has been done. The σ2R site was first characterized in pheochromocytoma PC12 cells, has a low affinity for (+)-BZM (benzomorphans), and has an apparent molecular weight of 18–21 kDa. The site also appears to be important in the modulation of cellular calcium [Ca2+] concentrations.

Several attributes have been proposed for σ2R sites: stem cell differentiation, regulation of motor functions, induction of dystonia after in situ administration in the red nucleus, and regulation of ileal function. The sites are also important in the blockade of tonic potassium [K+] channels, potentiation of the neuronal response to N-methyl-D-aspartate [NMDA] in the CA3 region of the rat dorsal hippocampus, or activation of a novel p53- and caspase-independent apoptotic pathway. This induction of apoptosis operates via a different mechanism distinct from other apoptotic stimuli.

Activation of the σ2R causes apoptosis via triggering of cancer selective cell death signaling by multiple pathways. The mechanism by which σ2R stimulation induces apoptosis may result from its modulation of intracellular Ca2+ stores in some tumors. This is of particular importance in those tumors that induce hypercalcemia, e.g., some lymphomas. It is for this reason that σ2Rs have been primarily investigated for possible use as cancer chemotherapy targets (Megalizzi et al. 2012).

Mechanism of Action

σ1Rs are intracellular receptors acting as chaperone proteins, which assist in the correct folding of other proteins, either during their synthesis or function. More specifically, σ1Rs modulate Ca2+ signaling through the inositol triphosphate [IP3] receptor. They dynamically translocate inside cells, hence are transmembrane proteins (Fig. 1). In fact, it has been suggested that the σ1R receptor at the mitochondrial-associated endoplasmic reticulum membrane is responsible for mitochondrial metabolic regulation, where σ1R promotes mitochondrial energy depletion, Ca2+ influx, and apoptosis (Marriott et al. 2012; Su et al. 2010). The σ1R chaperone protein can be activated or deactivated by specific ligands; thus, this chaperone is essential for the metabotropic receptor signaling and for the survival against cellular stress. σ2R is now thought to be a histone-binding protein (Hayashi and Su 2005; Pal et al. 2012).
Sigma Receptor (σR), Fig. 1

σRs and their effect on intracellular calcium concentrations

Although the precise mechanism of the biological response of σRs is still uncertain, it is accepted that σR can modulate a number of neurotransmitter systems, including neurosteroids, NMDA receptor-mediated, noradrenergic, and cholinergic, catecholaminergic, dopaminergic [DA] neurotransmitters thought to be especially important functional modulators of glutamate [Glu] activity at this site. σ1Rs, at least in part, are intracellular amplifiers creating a super sensitized state for signal transduction (Su and Hayashi 2003).

Manipulation of G-proteins alters σR-mediated effects on K+ currents, acid sensing ion channels, and NMDA-evokes release of [3H]norepinephrine. Yet this manipulation has no effect on K+ currents in other models, or on the NMDA response with other σR ligands. Contrasting evidence exists for the effects of G-proteins on σ1R ligand binding. Given the presumed heterogeneity of the σ1R subgroup, it is likely that one subtype of the σR interacts with G-proteins, while another subtype relies on G-protein-independent signal transduction mechanisms, probably via the NMDA receptor [NMDAR].


Studies on the modulation of ion channels by σ1Rs suggest that σ1Rs use G-proteins. Accordingly, the σ1R could interact functionally with G-proteins through a mechanism that differs from that of classical G-protein-coupled receptors. However, many physiological experiments suggest that σ2R signal transduction does not involve any G-protein.

The mechanisms of σR effects are not well understood, even though σ1Rs have been linked circumstantially to a wide variety of signal transduction pathways. Regardless of their involvement of G-proteins, it is more likely that σ1Rs act through the NMDAR rather than through these G-proteins.

Ion Channels and Cations

In support of the majority of effects of σ1R stimulation being mediated by the ionotropic glutamate receptors [iGluRs], such as the NMDAR, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor [AMPAR], and kainate receptor [KaR], the σ1R has been shown to appear in a complex with voltage-gated K+ channels, leading to the suggestion that these receptors are auxiliary subunits of the voltage gated channels.


σR-induced increases in Ca2+ currents, which develop progressively following relatively long-lasting applications of σR ligands, suggest a direct intracellular coupling of σR to Ca2+ channels, through which σR ligands can stimulate voltage-activated Ca2+ conductance, independent of the K+ channel pathway. In addition to reducing the peak amplitude of the Ca2+ current, σRs altered the kinetic properties of these channels. σ1R ligands modulate Ca2+ signaling by two different modes of action: intracellularly, perhaps on the ER, σ1R ligands potentiate bradykinin-induced increase in cytosolic free Ca2+ in a biphasic manner, which can be blocked by σ1R antisense oligodeoxynucleotide, and a second mode of action at the plasma membrane. It is possible that the major physiological function of the σ1R in the CNS is to regulate both types of intracellular Ca2+ equilibrium.

It has been proposed that the modulation of Ca2+ signaling mediated by σ1Rs involves the formation of a multiprotein complex, or σ1Rs that form multiunit complexes responsible for the modulation of these ion channels. Specifically, σ1Rs have recently been found to anchor ankyrin to the ER membrane and modulate the function of ankyrin and IP3 on the ER. In this model, the presence of an σR agonist leads to the σ1R-ankyrin complex dissociating from the IP3. This dissociation leads to an increased binding of IP3, which in turn increases Ca2+ efflux. On the other hand, in the presence of an σ1R antagonist the σ1R dissociates from ankyrin, which remains coupled to IP3 on the ER163. The σ2R subtype preferentially modulates Ca2+ entry (Kourrich et al. 2012).


Potassium conductance is the prominent target of σ1Rs with secondary messenger systems not being essential for the modulation of voltage-gated K+ channels by σ1R. Further investigations of this modulation suggest that a protein-protein interaction is the likely mechanism of signal transduction by σRs, as σR ligands do not interact directly with K+ channels, although this effect is enhanced in the presence of σR ligands. Therefore, σRs may serve as auxiliary subunits to voltage-gated K+ channels in the plasma membrane, which also may involve other proteins such as ankyrin and IP3R.

Studies on σ1R modulation of K+ channels, to date, have led to the conclusion that the signal transduction mechanism of σ1Rs is membrane independent of G-protein coupling and protein phosphorylation reconstructable in a heterologous system, not requiring cytoplasmic factors, and necessitating the σ1R and the K+ channel to be in close proximity, probably to form a stable macro-molecular complex (Fig. 2).
Sigma Receptor (σR), Fig. 2

Putative biological action of the σ1R on neuronal function

Once a neuron has been activated, e.g., via Glu or acetylcholine, a concomitant influx of Ca2+ and [Ca2+]i mobilization occur, facilitated by the activation of the endoplasmic-reticulum-bound σ1R, which is also triggered by numerous xenobiotics and steroids. The subsequent activation of phospholipase C and the recruitment of protein kinase C [PKC] from its inactive form [PKCi] to its active form [PKCa], which is translocated to the plasma membrane, result in the activation of various enzymatic processes, as well as the phosphorylation of membrane-bound neurotransmitter receptors. In turn, the σ1R translocates to the plasma membrane where it decreases the excitatory neurotransmitter-induced Ca2+ influx.

Activity Through Neurotransmitters

σ1Rs regulate a number of neurotransmitter systems, including the glutamatergic [Glu], dopaminergic [DA], serotonergic [5-HT], noradrenergic, and cholinergic systems. As these transmitters, which interact with the σ1Rs, are involved in many neuropsychiatric disorders, their role has been evaluated in a number of these disorders (Hayashi and Su 2004). As σRs are central to a number of CNS and other actions, it is not surprising that they interact with many other concurrent events within and outside the cell membranes on cells of many types. A functional interaction between σR ligands and neurosteroids, such as progesterone, glutamate receptor [GluR], opioids, DA, and 5-HT exist.

Neuroactive Steroids (Neurosteroids)

Neurosteroids, such as progesterone, pregnenolone, dihydroepiandrosterone, and their respective sulfate esters, are involved in regulating the imbalance between excitation and inhibition in the CNS. Neurosteroids rapidly alter neuronal excitability through interaction with neurotransmitter-gated ion channels, e.g., NMDA. Initially, it was proposed that steroids behave like endogenous σ1R ligands leading to the hypothesis that neurosteroids may constitute endogenous ligands for the σ1R. Early studies found that neurosteroids bind to σ1R but not to σ2R: only the human σ1R gene contains a steroid-binding component (Fig. 3). These neurosteroids are found in the cortex, hippocampus and brainstem, areas of the brain containing high densities of σ1R.
Sigma Receptor (σR), Fig. 3

Neurosteroids and their interactions with σRs


Opioids have subtle differences in binding to the μ, κ, and σRs; however, σRs are a receptor class in their own right. Although σRs now have been classified as a separate group of receptors from the opioid receptors, the outcome of σR binding is not necessarily different from that when these receptors are bound to opiates (Fig. 4), especially since interactions between κ receptors and σRs have been reported.
Sigma Receptor (σR), Fig. 4

A schematic representation of the opioid receptor and σ1Rs


There is controversial evidence regarding possible interactions between σR and the 5-HT system (Fig. 5). 5-HT and tryptophan play a key role in depression and the mechanism of action of many antidepressants, probably via a decrease in the firing activity of 5-HT neurons. Research findings suggest modulation of 5-HT neurotransmission by σR ligands in vivo probably mediated by σ1Rs via the 5-HT1A receptor.
Sigma Receptor (σR), Fig. 5

Serotonin (5HT) stimulation of the σ1R


The σ1R subtype is involved in the facilitation of cortical DA transmission, where σ1R ligand agonists increase extracellular DA levels in rats. Conversely, their antagonism inhibits DA-induced abnormal involuntary movements. σRs may regulate the release of DA along with an action at the NMDAR, e.g., the pharmacological effects of amantadine on DAergic transmission are proposed to result from an uncompetitive antagonism at this receptor. Activation of σ2R results in the regulation of dopamine transporter activity via a Ca2+- and PKC-dependent signaling mechanism.

Nicotine and Acetyl Choline

σ1R ligands noncompetitively inhibit nicotine-stimulated catecholamine release in a concentration-dependent and reversible manner. The rank order of potency of ligands to inhibit nicotine stimulated catecholamine release is correlated with that observed in radioligand binding assays selective for the σ1R subtype. σR ligands are without effect on catecholamine release or [Ca2+]i in the absence of nicotine, although the inhibitory effect of σR ligands on the nicotine-evoked Ca2+ uptake is not directly coupled with either the σ1R or σ2R sites. Thus, the actions of agonists at the nicotinic acetylcholine receptor are modulated by σ1R selective ligands.

Nitric Oxide

σR ligands prevent Glu-induced activation of nitric oxide synthetase [NOS], an important mediator in ischemic brain injury, and in many other disease states. Specifically, nitric oxide [NO] derived from constitutively expressed NOS in neurons [nNOS] and the inducible isoform expressed by many cells [iNOS] are important in excitotoxic injury cascades, such as can be seen following exposure to excitatory amino acids. It is not surprising that systemic σR ligand treatment reduces stroke damage by preventing ischemia-induced NO production with reduced infarct volume. For this reason, it has been suggested that σ1R agonists should be considered as neuroprotective drugs, where some of the protection offered occurs through inhibition of inducible NOS.


σRs mediate a number of processes through the Glu system (Fig. 6). At toxic concentrations, Glu acts as a neurotoxin (excitatory amino acid) capable of inducing severe neuronal damage and necrosis by causing over excitation of neurons through receptor-mediated depolarization and Ca2+ influx. The Glu system is probably the mediator of excitatory effects seen following σRs stimulation and neuroprotection following antagonism of σRs. It is now clear that the σRs are important in modulating Glu-mediated seizures, and protects neurons against Glu toxicity in vitro, although direct interaction with NMDARs should not be forgotten as a crucial element in the neuroprotective effects of σRs ligands with affinity for NMDARs.
Sigma Receptor (σR), Fig. 6

Interaction of glutamate, neurotransmitters, and the σR

The NMDAR is perhaps the best characterized of the iGlu, in part due to the existence of selective agonists and antagonists that can be used to study its physiology. These receptors are modulated by σ1R. NMDAR are highly permeable for Ca2+. They show slower gating kinetics with the channel blocked in a voltage and use-dependent manner by physiological concentrations of magnesium ions. It is this property of the NMDAR that enables σRs to trigger cell death via Ca2+ overload. It should be noted, however, that the effects of all σ1R agonists on the NMDA response produce a biphasic dose-response curve. Overall, many σ1R ligands have demonstrated the ability to modulate NMDA-mediated Glu neurotransmission.


Cannabis and cannabinoids exert most of their biological functions through receptor-mediated mechanisms. Two types of cannabinoid receptors [CB] have been identified – namely CB1 and CB2 – both coupled to a G protein. CB1 receptors have been detected and quantified in the CNS. CB1 cannabinoid receptors appear to mediate most, if not all of the psychoactive effects of δ-9-tetrahydrocannabinol and related cannabinoid compounds. This G protein-coupled receptor has a characteristic distribution in the nervous system: it is particularly enriched in cortex, hippocampus, amygdala, basal ganglia outflow tracts, and cerebellum, a distribution that corresponds to the most prominent behavioral effects of cannabis.

Cannabinoid CB2 receptors have only been detected outside the central nervous system, mostly in cells of the immune system, presumably mediating cannabinoid-induced immunosuppression and anti-inflammatory effects. With the discovery of cannabinoid receptors for exogenous cannabinoids, endogenous cannabinoids (anandamide, 2-arachidonylglycerol [2-AG]) have been described subsequently.

The relationship of cannabinoids to the σRs has received little attention, although CB1 has been shown to interact with the classical opiate receptors. Although studies seldom include investigation of the σRs, the effects on other neurotransmitter systems suggest a possibility of interaction of the CB and σRs. CB1 receptor agonists damp the excitatory effects of Glu. Although specific, direct data are absent for the role that σRs play in the cannabinoid modulation, the role that σRs play in Glu modulation suggests that they are probably involved in the modulation of Glu produced by the endocannabinoids.


Summarizing the interactions of σR with neurotransmitters is difficult. Data are scarce and incomplete. In addition, the dose-response of stimulation of the σR to an agonist can show stimulatory effects at a low dose and inhibitory effects at high doses, when used experimentally using greater concentrations than physiological levels. As most work is done in in vitro, doses are often excessive and may reflect an overexposure that would not be seen in the in vivo situation. Nonetheless, it seems clear that the σRs have a core and only partly defined role in regulation of neurotransmission.


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Authors and Affiliations

  1. 1.Department of Pathology and Laboratory Medicine, Faculty of MedicineUniversity of OttawaOttawaCanada