Journal of Pharmacological Sciences 127 (2015) 2e5

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Journal of Pharmacological Sciences

journal homepage: www.elsevier.com/locate/jphs

Current perspective

Sigma-1 receptor: The novel intracellular target of

neuropsychotherapeutic drugs
Teruo Hayashi*
Seiwakai Nishikawa Hospital, 293-2 Minato-machi, Hamada, Shimane 697-0052, Japan

a r t i c l e i n f o

a b s t r a c t

Article history:
Received 23 May 2014
Received in revised form
18 July 2014
Accepted 23 July 2014
Available online 9 December 2014

Sigma-1 receptor ligands have been long expected to serve as drugs for treatment of human diseases
such as neurodegenerative disorders, depression, idiopathic pain, drug abuse, and cancer. Recent
research exploring the molecular function of the sigma-1 receptor started unveiling underlying mechanisms of the therapeutic activity of those ligands. Via the molecular chaperone activity, the sigma-1
receptor regulates protein folding/degradation, ER/oxidative stress, and cell survival. The chaperone
activity is activated or inhibited by synthetic sigma-1 receptor ligands in an agonist-antagonist manner.
Sigma-1 receptors are localized at the endoplasmic reticulum (ER) membranes that are physically
associated with the mitochondria (MAM: mitochondria-associated ER membrane). In specic types of
neurons (e.g., those at the spinal cord), sigma-1 receptors are also clustered at ER membranes that
juxtapose postsynaptic plasma membranes. Recent studies indicate that sigma-1 receptors, partly in sake
of its unique subcellular localization, regulate the mitochondria function that involves bioenergetics and
free radical generation. The sigma-1 receptor may thus provide an intracellular drug target that enables
controlling ER stress and free radical generation under pathological conditions.
2014 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords:
Sigma receptor
Sigma-1 receptor
ER stress
MAM
Chaperone

1. Introduction
In the early 1970s, Martin proposed the sigma receptor as one of
the opioid receptor subtypes (i.e., sigma opioid receptor), by which
the psychotomimetic action of benzomorphans is mediated (1,2).
However, following studies had conrmed that the sigma receptor is
a non-opioid, non-G protein-coupled, intracellular protein (2,3).
Binding assay studies found that the sigma receptor consists of at
least two subtypes: sigma-1 and sigma-2 receptor (4). Although the
molecular entity and structure were totally unclear until the late
1990s (3), early studies indicated that the sigma-1 receptor may
exert therapeutic activities by interacting with several psychoactive
drugs, such as haloperidol and selective serotonin uptake inhibitors
(SSRIs) (1,5). Further, preclinical studies demonstrated that sigma
receptor ligands modulate neuroprotection, cancer growth, ion
channel activities, and animal behaviors implicated in memory/
cognition, mood, pain, and drug abuse (6e8). Recent advances in
molecular biology of the sigma receptor begin elucidating molecular
* Tel.: 1 81 855 22 2390; fax: 1 81 855 22 3680.
E-mail address: thayashi2r@gmail.com.
Peer review under responsibility of Japanese Pharmacological Society.

mechanisms by which sigma-1 receptor ligands exert these varieties

of actions (2). In this review, rstly molecular pharmacological roles
of the sigma-1 receptor are summarized, and then a potential future
direction of this research eld is discussed.
2. Molecular biology of the sigma-1 receptor
From the 1970s to 1990s, hypotheses that tempted to explain the
entity of the sigma receptor were proposed: e.g., the opioid receptor subtype hypothesis and the MK801-binding site hypothesis
(1,9). However, since radio-ligand binding assays were the only tool
to assay the sigma-1 receptor in those days, it was difcult to
experimentally and conclusively prove those hypotheses. Therefore, even the existence of the sigma-1 receptor protein was not
fully conrmed and accepted. But the debate on the entity of the
sigma-1 receptor nally ended in 1996 by the successful cloning of
the sigma-1 receptor gene (3). Thanks to the groundbreaking discovery, molecular biological approaches were since then actively
introduced to this research eld.
The cloning study demonstrated that the sigma-1 receptor
consists of 223 amino acids with two potential trans-membrane
domains (3). In agreement with the fact that the protein

http://dx.doi.org/10.1016/j.jphs.2014.07.001
1347-8613/ 2014 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://
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T. Hayashi / Journal of Pharmacological Sciences 127 (2015) 2e5

possesses a double-arginine ER retention signal at the N-terminus,

several recent studies conrmed the ER localization of sigma-1
receptors (10,11). So far, only few electron microscopic data is
available that clearly demonstrates the signicant plasma membrane localization of the sigma-1 receptor (12,13). The second
trans-membrane domain and the C-terminus of the sigma-1 receptor in the ER lumen are proposed to form the ligand-binding site
(14). Therefore, in contrast to the majority of ligand-binding sites of
neurotransmitter receptors, the binding site of the sigma-1 receptor is located in the inner ER membrane or the lumenal surface of
the ER membrane. The unique hydrophobic environment of the
ligand-binding site may be enabling hydrophobic molecules to
associate with the binding site. Indeed, the most sigma-1 receptor
ligands possess hydrophobic or amphipathic property (e.g., haloperidol and uvoxamine) (1,5). Postulated endogenous ligands of
the sigma-1 receptor include steroids (e.g., progesterone, DHEAsulfate), hallucinogen N,N-dimethyltrypatamine, and sphingosine
(15e17). Furthermore, a recent study suggested a possibility that
monoglycosylated ceramide might possess a high afnity for the
sigma-1 receptor (18). Among sigma-1 receptor-binding lipids,
steroids (e.g., progesterone and testosterone, DHEA) seem to have
relatively low afnities (0.3e10 mM) when compared with those of
endogenous sphingolipids and monoglycosyated ceramides
(15,17,18). Certain sphingolipids appear to possess afnities high
enough to bind sigma-1 receptors at their physiologically relevant
concentrations.
A recent study found that, upon its binding to sigma-1 receptors,
the highly selective sigma-1 agonist () pentazocine promotes the
association of sigma-1 receptors with Insig-1, the SREBP escorting
protein localized at the ER (19). Notably, 25-dehydorxylcholesterol

exerts the same effect at nM concentrations (19). Though further

studies are necessary for conrmation, the data suggests that 25hydroxycholesterol might serve as a high-afnity endogenous
ligand for the sigma-1 receptor.
3. The sigma-1 receptor is a novel ligand-operated molecular
chaperone (Fig. 1)
The sigma-1 receptor shares no homology with any mammalian
protein (3). This fact made it difcult to predict the molecular
function of the sigma-1 receptor from the amino acid sequence.
Nonetheless, a combination of subcellular localization studies,
protein purication studies, coupling proteins identication, and
in vitro protein activity assays, has begun to reveal the molecular
function of the sigma-1 receptor. It was demonstrated that the Cterminus of the sigma-1 receptor possesses a molecular chaperone
activity that stabilizes ER proteins, thus being able to regulate their
degradation (10,20). The association of another ER chaperone BiP
regulates the chaperone activity of the sigma-1 receptor (10). The
sigma-1 receptor forming a complex with BiP is in a dormant state,
whereas the free sigma-1 receptor that dissociates from BiP exerts
maximum chaperone activity (10). The association between sigma1 receptors and BiP is Ca2-dependent, and thus the depletion of ER
Ca2 activates the sigma-1 receptor chaperone (10). Importantly,
even in the presence of ER Ca2, sigma-1 receptor agonists cause
the dissociation of BiP from sigma-1 receptors, leading to activation
of sigma-1 receptor chaperones (10). It was also demonstrated that
sigma-1 receptor antagonists inhibit the action of agonists (10).
Therefore, synthetic drug that can associate with sigma-1 receptors
activate or inhibit the sigma-1 receptor's chaperone activity.

Fig. 1. Molecular functions of the sigma-1 receptor. The sigma-1 receptor possesses two transmembrane domains and mainly localize at the ER membrane. Sigma-1 receptors are
clustered at the mitochondria-associated ER membrane (MAM) and ER membranes juxtaposing postsynaptic density of specic types of neurons. The ER lumenal domain of the
sigma-1 receptor exerts chaperone activities by which ER membrane proteins are stabilized. The gure depicts the recently reported actions of the sigma-1 receptors including: 1)
Sigma-1 receptors associating with BiP stabilizes IP3 receptors type-3 (IP3R) at the MAM, leading to regulation of Ca2 inux into mitochondria and following ATP production; 2)
Sigma-1 receptors stabilize the ER stress sensor IRE1 at the the MAM in an ROS-dependent manner, leading to prolongation of the IRE1-XBP1 cell survival signal; 3) Sigma-1
receptors suppress generation of reactive oxigen species (ROS) and following activation of the NFkB signaling (How the sigma-1 receptor regulates ROS generation is unknown); 4) Sterols such as 25-hydroxycholesterol promote the association of sigma-1 receptors with Insig-1 [Collaborating with Insig-1, sigma-1 receptors regulate ER-associated
degradation (ERAD) of HMG-CoA reductase and galactosylceramide synthase at the ER]; 5) Sigma-1 receptors regulate the trafcking of potassium channel subunits from the ER to
the plasma membrane or processing/secretion of brain-derived trophic factor (BDNF). Sigma-1 receptors likely associate with potassium channel subunits or pro-BDNF at the ER. In
spinal neurons, sigma-1 receptors, which colocalize with a K channel subunit are clustered at the ER membrane apposing postsynaptic densities (PSD). How the sigma-1 receptor
regulates processing/secretion of BDNF is unknown.

T. Hayashi / Journal of Pharmacological Sciences 127 (2015) 2e5

4. The sigma-1 receptor is the regulator of the inter-organelle

communication (21)
As previously mentioned, the primary location of sigma-1 receptors is the ER membrane (2). A line of studies demonstrated that
sigma-1 receptors tend to form clusters and are highly enriched at
specialized subdomains of ER membranes. For example, in Chinese
hamster ovary (CHO) cells, sigma-1 receptors localize onto the ER
membrane that is physically associated with mitochondrial outermembrane (MAM: the mitochondria-associated ER membrane)
(10). Recent studies indicated that membrane lipids, such as
cholesterol and sphingolipids, play a role in recruiting sigma-1
receptors to the MAM (18). In contrast to the bulk ER membranes
that contain few cholesterol and sphingolipids, the MAM contains
considerable levels of ceramides and cholesterol, thus forming lipid
raft-like microdomains (18,22,23). Certain sterols and sphingolipids, which bind to sigma-1 receptors, may thus contribute to
promoting sigma-1 receptors to the MAM (Fig. 2).
The MAM is known to play a role as a center that directly provides Ca2 or phospholipids to the mitochondria. Ca2 provided by
MAM-localized IP3 receptors activates the TCA cycle, thus causing
ATP production (20). One of proven mechanisms of the sigma-1
receptor is to stabilize IP3 receptors at the MAM for proper Ca2
ux from the MAM into mitochondria (Fig. 1) (10).
Most recently, it is found that IRE1, one of the ER stress sensor
proteins, are enriched at the MAM and stabilized by sigma-1 receptors, especially during the early stage of ER stress (Fig.1) (24). The
stabilization of IRE1 by sigma-1 receptors prolongs the ER-to-nucleus
signal, mediated by XBP1 for cellular survival (24). The study also
suggests that the IRE1-sigma-1 receptor complex is equipped to the
MAM to monitor mitochondria-generated reactive oxygen species
(ROS) (24). It is shown that upon generation of ROS at the mitochondria sigma-1 receptors begin to associate with IRE1 for the
stabilization of IRE1 and prolonging the IRE1-XBP1 signaling (24).
Though the underlying mechanism is unclear, a line of studies
demonstrated that sigma-1 receptors function as a suppressor of
ROS generation. The knockdown of sigma-1 receptor per se causes
the accumulation of ROS and activation of the downstream
pathway involving NFkB (25). In contrast, sigma-1 receptor upregulation are shown to cause inhibition of ROS generation under
pathological conditions (25).
It is noteworthy that a recent study found that sigma-1 receptors in spinal mouse motor neurons are localized to subsurface

structures of cholinergic postsynaptic densities (12), suggesting

that ER membranes juxtaposing postsynaptic plasma membranes
are highly enriched with sigma-1 receptors in those neurons.
Interestingly, those sigma-1 receptors are co-localized with Kv2.1
potassium channels (12). Another set of studies recently found that
sigma-1 receptors regulate cocaine-induced behavioral sensitization by regulating expression of cell surface Kv1.2 in the nucleus
accumbens (26), postulating that sigma-1 receptors at the ERplasma membrane interface might regulate the trafcking of potassium channels (Fig. 1). An in vitro study demonstrated that
sigma-1 receptors regulate processing/trafcking of pro-brainderived neurotrophic factor (BDNF) (Fig. 1) (27).
More studies are certainly necessary to elucidate molecular
mechanisms by which sigma-1 receptors at the ER preferentially
localize to interfaces between the ER and other organelles. Nonetheless, the unique subcellular localization of sigma-1 receptors
and their regulating signaling pathways at organelle-to-organelle
interfaces suggest that the sigma-1 receptor serves as a modulator of inter-organelle communications that are mediated by direct
membrane associations.
5. Why does the sigma-1 receptor possess two transmembrane domains?
Molecular chaperones are mostly water-soluble proteins lacking
trans-membrane domains. The water-soluble property is advantageous for them to move freely in the cytoplasm or in organelle lumens as well as in accessing freely to miss-folded proteins. One of the
fundamental questions regarding the molecular biology of the sigma1 receptor is, Why does the sigma-1 receptor possess two transmembrane domains that may potentially restrict their movement
at the ER. One possible answer to this question is that sigma-1 receptors are localized to the ER membrane to stabilize ER membrane
proteins that mediate the signaling/transport across the ER membranes. For instance, sigma-1 receptors at the ER membranes chaperone IP3 receptors and IRE1, both of which are transmitters of ERderived signals (i.e., Ca2 released via IP3 receptors, XBP1 mRNA
splicing mediated by IRE1's endonuclease activity) (10,24). Perhaps
sigma-1 receptors, by associating with membrane proteins, directly
commit to regulations of signals across the ER membranes (Fig. 3).
The other possible answer is that the trans-membrane domain of the
sigma-1 receptor is possibly being utilized to form protein complexes
(Fig. 3). A recent study found that the second trans-membrane

Fig. 2. The hypothetical scheme depicting topology of membrane lipids and the sigma-1 receptor at the MAM. In contrast to the bulk of ER membranes that has the symmetric
transbilayer lipid distribution, the MAM may comprise more heterogeneous lipid distribution by accommodating simple sphingolipids and cholesterols, thus leading to the
formation of lipid raft-like microdomains. The ceramide-rich lipid microdomains may be predominantly localized at the lumenal leaet of the MAM. Microdomains may promote
the recruitment of specic ER proteins such as the sigma-1 receptor (red) to the MAM. In specic cell types (e.g., oligodendrocytes), galactosylceramides, which are synthesized at
the ER lumen, might substitute with ceramides in the MAM-localizing lipid microdomains. GlcCer, glucosylceramide; PtSer, phosphatidylserine; PtEt, phosphatidylethanolamine;
PtChol, phosphatidylcholine.

T. Hayashi / Journal of Pharmacological Sciences 127 (2015) 2e5

Fig. 3. The potential mechanism of the membrane-associated sigma-1 receptor

chaperone. The membrane-spanning structure of the sigma-1 receptor chaperone may
be advantageous to stabilize ER membrane proteins that are involved in regulation of
the signaling/transport across ER membranes (e.g., IP3 receptors, IRE1). As shown in
the case of its association with Insig-1, the second trans-membrane domain of the
sigma-1 receptor is possibly being utilized for the association with client proteins.
Residues 116e176 may contain a putative chaperone domain (red), whereas resides
198e206 comprise a putative membrane attachment region (light blue) (28). Numbers
placed on the sigma-1 receptor indicate positions of respective amino acid residues.

domain of the sigma-1 receptor is necessary for its association with

Insig-1, the ER sterol-sensor regulating SREBP-mediated transcriptions of lipid enzymes (19). The sigma-1 receptor, by forming a
complex with Insig-1, mediates ER-associated degradation (ERAD) of
specic sets of ER proteins that bind to sterols (e.g., HMG-CoA
reductase, galactosylceramide synthase) (19).
6. Conclusion
In the last fteen years, the understanding of the function of the
sigma-1 receptor was signicantly advanced, particularly at the
molecular level. The sigma-1 receptor localized at the ER modulates
via its chaperone activity inter-organelle communications. Sigma-1
receptors thus regulate a variety of cellular events, such as neuronal
differentiation, cellular survival, and bioenergetics. By numerous
animal studies, these actions of the sigma-1 receptors have been
linked to the pathophysiology of certain human diseases such as
depression, ischemia, drug abuse, pain, and cancer. Considering the
current pharmacotherapy of neuropsychiatric diseases that largely
depends on drugs developed based on the monoamine theory, the
sigma-1 receptor is expected to serve as a molecule, which provides
a novel target of post-monoamine drugs, thus bringing a new
approach for treatment of patients suffering from neuropsychiatric
diseases.
Conicts of interest
The author indicated no potential conicts of interests.
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