TIPS 1304 No.

of Pages 17

Opinion
The Sigma-1 Receptor as
a Pluripotent Modulator in
Living Systems
Tsung-Ping Su,1,* Tzu-Chieh Su,1 Yoki Nakamura,1 and
Shang-Yi Tsai1
The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum (ER) protein that
Trends
resides specifically in the mitochondria-associated endoplasmic reticulum (ER)
Sig-1R occurs specifically at the MAM,
membrane (MAM), an interface between ER and mitochondria. In addition to the interface between the ER and mito-
being able to translocate to the plasma membrane (PM) to interact with ion chondria, where it promotes cellular
survival.
channels and other receptors, Sig-1R also occurs at the nuclear envelope,
where it recruits chromatin-remodeling factors to affect the transcription of Upon stimulation by agonists or stres-
genes. Sig-1Rs have also been reported to interact with other membranous sors, Sig-1R can translocate to the PM
to interact with ion channels, receptors,
or soluble proteins at other loci, including the cytosol, and to be involved in and kinases.
several central nervous system (CNS) diseases. Here, we propose that Sig-1R is
Experimental and bioinformatics studies
a pluripotent modulator with resultant multiple functional manifestations in
have identified interactions between
living systems. Sig-1R and other functional proteins in
the PM, ER, mitochondria, and even the
cytosol.
The Sigma-1 Receptor: Brief History and Current Status
Martin et al. [1] hypothesized the existence of multiple opioid receptors to mediate different CNS diseases have been reported to
relate to Sig-1R, including Alzheimer's
pharmacological effects of morphine and its various structural analogs. These receptors and
disease, Parkinson's disease, amyo-
their prototypic ligands and pharmacological effects are: mu opioid receptor (MOR) for mor- trophic lateral sclerosis, Huntington's
phine-induced analgesia, kappa opioid receptor for ketocyclazocine-induced dysphoria, and disease, stroke/ischemia, pain/neuro-
sigma ‘opioid’ receptor for SKF-10047 (N-normetazocine)-induced psychotomimesis. Influ- pathic pain, and certain psychiatric
disorders.
enced by the multiple opioid receptor hypothesis, Su [2] demonstrated the existence of a
‘sigma receptor’ that differs from Martin et al.’s sigma ‘opioid’ receptor in that the former has low Pharmacological or cellular engineering
affinity for naltrexone, which is a universal high-affinity blocker for all opioid receptor subtypes, as targeting Sig-1R may provide thera-
hypothesized by Martin et al. peutic opportunities to treat such
diseases.

Therefore, the sigma receptor discovered by Su is a receptor type on its own rather than an
opioid receptor subtype. Unfortunately, this receptor was mistermed as the sigma ‘opioid’
receptor in its original publication [2] but was later correctly called the ‘sigma receptor’ [3]. The
sigma receptor was later recognized as Sig-1R, and two subtypes of the sigma receptor were
identified as Sig-1R and Sig-2R [4]. Sig-1R has been cloned and was found to be an ER
protein (Box 1) [5]. Sig-2R has not yet been cloned. Although the progesterone receptor 1
Cellular Pathobiology Section,
membrane component 1 was suggested to be Sig-2R [6], its final identification remains to be Integrative Neuroscience Research
fully clarified. Branch, Intramural Research Program,
National Institute on Drug Abuse,
National Institutes of Health,
Sig-1R is mainly an ER protein, where it resides specifically at the MAM [7]. At the MAM, Sig-1R Department of Health and Human
acts as a molecular chaperone and sustains the correct conformation of the inositol triphosphate Services, Baltimore, MD 21224, USA

(IP3) receptor type 3 to ensure proper Ca2+ signaling from the ER into mitochondria to facilitate
the production of ATP [7–9]. At the MAM, Sig-1R also chaperones an ER stress sensor, inositol- *Correspondence:
requiring enzyme 1 (IRE1), to ensure the correct transmission of ER stress into the nucleus, TSU@intra.nida.nih.gov (T.-P. Su).

Trends in Pharmacological Sciences, Month Year, Vol. xx, No. yy http://dx.doi.org/10.1016/j.tips.2016.01.003 1

Published by Elsevier Ltd.
 TIPS 1304 No. of Pages 17

Box 1. Status Quo of the Sigma-1 Receptor

Sig-1R was cloned in 1996 and was found to bear no sequence resemblance to any mammalian proteins. It was later
discovered that the Sig-1R resides specifically at the ER-mitochondrion interface called the MAM where and beyond the
Sig-1R participates in diverse actions critical to cellular survival and certain diseases.

Sig-1R exists at the MAM, where it promotes cellular survival by: (i) ensuring Ca2+ signaling from the ER into mitochondria
by chaperoning the IP3 receptor; (ii) enhancing ER–nucleus signaling to induce antioxidant release by chaperoning the ER
stress sensor IRE1; and (iii) attenuating free radical damage through Nrf2 signaling.

Upon stimulation by agonists, Sig-1R can also translocate from the MAM to the PM, where it interacts with, and affects
the function of, many other receptors, ion channels, and kinases. Sig-1R can also translocate to the nuclear envelope,
where it recruits chromatin-remodeling factors to affect the transcriptional regulation of genes. In addition, Sig-1Rs have
been reported to interact with other membranous and soluble functional proteins in other parts of the cell, including the
cytosol. Thus, Sig-1R may represent a pluripotent modulator in living systems. Being a pluripotent modulator also means
that, most likely, the action of Sig-1R may not be apparent until the living system is under abnormal state such as the
beginning of disease formation that calls for the Sig-1R to go into action to assist. Any behavioral design to test for the
influence of Sig-1R in the living system should perhaps bear this important point in mind.

Sig-1R has been shown to relate to many diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic
lateral sclerosis, Huntington's disease, stroke/ischemia, pain/neuropathic pain, certain psychiatric disorders, cocaine
addiction, myocardial hypertension, and cancer. Thus, inasmuch as Sig-1R acts as a pluripotent modulator, its
dysfunction may have a role in those diseases. Therefore, pharmacological or cellular engineering targeting Sig-1R
may provide therapeutic opportunities to treat these diseases.

resulting in the enhanced production of antistress and antioxidant proteins [10]. Sig-1Rs also
attenuate the formation of reactive oxygen species (ROS) by enhancing the signaling of Nrf2 [11].

Upon the stimulation of agonists or stressors, Sig-1R can translocate to the PM to interact with
ion channels, receptors, and kinases [12,13]. Sig-1R was also found to translocate to the
envelope of the nucleus [14,15], where it interacts with emerin, a nuclear envelope-resident
protein, and recruits a series of chromatin-remodeling factors to regulate gene transcription [15].
Recently, many experimental and bioinformatic studies have identified or proposed the interac-
tion of Sig-1R with other functional proteins in the PM, ER, mitochondria, and even the cytosol.

Taken together, the above results suggest that Sig-1R acts as a pluripotent modulator in living
systems and, thus, may be involved in human diseases. In this Opinion, we highlight those
proteins that have been experimentally shown to interact with Sig-1R (Figure 1), and other
proteins that have been reported to link to Sig-1R based on bioinformatic studies (Figure 2). We
also show in particular the CNS diseases that have been reported to relate to Sig-1R (Table 1).
Collectively, current research findings suggest that Sig-1R, as a pluripotent modulator via its
interactions with diverse classes of other proteins, has important physiological roles in living
systems and that its dysfunction contributes to several human diseases.

Experimentally Demonstrated Sig-1R-Interacting Proteins

At the Plasma Membrane
Regardless of its predominant ER membrane expression pattern, many reports have demon-
strated that Sig-1R also regulates PM proteins (Figure 1). Here, we briefly review the PM proteins
that have been reported so far to interact directly with the Sig-1R.

Acid-Sensing Ion Channels (ASICs)

ASICs are proton-gated cation channels expressed in the peripheral nervous system and CNS
that can be activated by acidic pH conditions that occur, for example, during ischemia.

Sig-1Rs can modulate ASICs via the activation of the former by ligands resulting in, for example,
the inhibition of ASIC1a-induced calcium influx in rat cortical neurons [16]. Direct interactions
between Sig-1Rs and ASIC1a were later demonstrated by atomic force microscopy (AFM).

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Plasma membrane

ASIC Kv1.2 Kv1.3 Kv2.1 Nav1.5 hERG NR1 D1R D2R MOR CB1R TrkB PDGFR ITG-β1

Insig
ELMOD

MAM

GRP78/Bip/ RanBP2
HSPAS
Emerin
ER
IRE1
Mitochondria
Rac1

Nucleus
VDAC2
Ankyrin

IP3R

Figure 1. Experimentally Determined Sigma-1 Receptor (Sig-1R)-Interacting Proteins. Sig-1R is shown as a two-
transmembrane protein in black. ER, endoplasmic reticulum; MAM, mitochondrion-associated ER membrane. Abbrevia-
tions: (A) at the plasma membrane: ASIC, acid-sensing ion channel; CB1R, cannabinoid receptor 1; D1R, dopamine
receptor 1; D2R, dopamine receptor 2; hERG, voltage-gated potassium channel hERG (human ether-à-go-go related
gene); Kv1.2, Kv1.3, and Kv2.1, voltage-gated potassium channel; MOR, mu opioid receptor; Nav1.5, voltage-gated
sodium channel; NR1, NMDA receptor subunit 1; PDGFR, platelet-derived growth factor receptor; TrkB, Tropomyosin
receptor kinase B for brain-derived neurotrophic factor. (B) In the cytosol, general ER membrane, or mitochondrial outer
membrane: ELMOD, cell engulfment and motility domain; Insig, insulin-induced gene; Rac1, Ras-related C3 botulinum toxin
substrate (Rac)-GTPase. (C) At MAM: GRP78/BiP/HSPA5, glucose response protein/immunoprotein-binding protein/heat
shock protein A5; IRE1, inositol-requiring enzyme 1; IP3R, inositol trisphosphate receptor; VDAC, voltage-dependent anion
channel 2. (D) At the nuclear envelope: RanBP2, Ran-binding protein 2.

Analysis of the binding of Sig-1R to ASIC1a was carried out in cells coexpressing ASIC1a and
FLAG/His6-tagged Sig-1R. The stoichiometry results suggested that Sig-1R associates with the
trimeric ASIC1a subunit with a threefold symmetry [17]. However, opinions differ as to whether
the interaction of Sig-1R and ASIC1a occurs in lipid rafts.

Dopamine Receptors (DR)

DR have crucial roles in many neurological processes, including motivation, cognition, memory,
and motor function. There are at least five DR subtypes (D1R, D2R, D3R, D4R, and D5R), which
are grouped as D1-like receptors (D1R and D5R) and D2-like receptors (D2R, D3R, and D4R),
which stimulate or inhibit adenylyl cyclase, respectively.

Navarro and colleagues [18] demonstrated the heterodimerization of Sig-1R and D1R in living
cells using bioluminescent resonance energy transfer saturation experiments. Colocalization of
Sig-1R and D1R was also identified by immunostaining studies. The Sig-1R–D1R interaction
was later extended to animal tissue, where Sig-1R–D1R–Histamine H3 receptor complexes
were detected in rat striatum by energy transfer experiments and proximity ligation assays [19]. A
similar approach was applied to establish the functional interaction of Sig-1R and D2R. The data
suggest that cocaine binds to Sig-1R–D2R heteromers and inhibits the downstream extracel-
lular signal-regulated kinase (ERK)–mitogen-activated protein kinase (MAPK) signaling pathway
[20]. These findings also suggest that Sig-1R binds D1R and D2R and, thus, differentially

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Plasma membrane:
PDZD11*
TM7SF2*

Cytoplasm:
EIF5A* ER membrane
HSPA5* AUP1
NACA2* C14orf1
PDZD11*
Golgi:
CYP51A1
GANAB*
RAF1* CFTR
RPS27A* SURF4*
EIF5A*
SEC61A2 GANAB*
TM7SF2* HSD17B12
UBA52* HSPA5*(ER lumen)
UBC* NSDHL*(lipid droplit)
XPO1* RDH11
XPOT* RPN2
SC4MOL
SEC61A2
SQLE Nucleus:
SURF4* CYC1
TM7SF2* CLN3
EIF5A*
Mitochondria: LBR (inner membrane)
CYC1 (inner membrane) NACA2*
PHB (inner membrane) NUP205
SLC25A11 (inner membrane) RAE1*
SLC25A39 (inner membrane) RNP2
VSAC2 (outer membrane) RPS27A*
UBA52*
UBC*
XPO1*
XPOT*

Figure 2. Proposed Sigma-1 Receptor (Sig-1R)-Interacting Proteins Based on Bioinformatic Analyses [61].
*Indicates that a protein has multiple locations. Abbreviations: AUP1, ancient ubiquitous protein 1; C14orf1, chromosome
14 open reading frame 1; CYC1, cytochrome c-1; CYP51A1, cytochrome P450, family 51, subfamily A, polypeptide 1;
EIF5A, eukaryotic translation initiation factor 5A; ER, endoplasmic reticulum; GANAB, glucosidase, alpha; neutral AB;
HSD17B12, hydroxysteroid (17-beta) dehydrogenase 12; HSPA5, heat shock 70-kDa protein 5; glucose-regulated protein,
78 kDa; BIP; LBR, lamin B receptor; NACA2, nascent polypeptide-associated complex alpha subunit 2; NSDHL, NAD(P)-
dependent steroid dehydrogenase-like; NUP205, nucleoporin 205 kDa; PHB, prohibitin; PDZD11, PDZ domain-containing
11; RAE1, RAE1 RNA export 1 homolog; RDH11, retinol dehydrogenase 11 (all-trans/9-cis/11-cis); RPS27A, ribosomal
protein S27a; RPN2, ribophorin II; SC4MOL, sterol-C4-methyl oxidase-like; SEC61A2, Sec61 alpha 2 subunit (Sacchar-
omyces cerevisiae); SLC25A11, solute carrier family 25 (mitochondrial carrier; oxoglutarate carrier) member 11; SLC25A39,
solute carrier family 25, member 39; SQLE, squalene epoxidase; SURF4, surfeit 4; TM7SF2, transmembrane 7 superfamily
member 2; UBA52, ubiquitin A-52 residue ribosomal protein fusion product 1; UBC, ubiquitin C; VDAC2, voltage-
dependent anion channel 2; XPO1, exportin 1 (CRM1 homolog, yeast); XPOT, exportin(tRNA) (nuclear export receptor
for tRNAs).

Table 1. Sig-1R-Associated CNS Diseases

Disorders Interacting Proteins and Potential Locations Refs

Amyotrophic lateral sclerosis BiP (ER), Insig (ER), RanBP2 (NE), mAchR (PM) [65,66,75–93]
(ALS)/motor neuron disorders

Alzheimer's disease (AD) Rac-GTPase (mitochondria), BiP (ER and [57,67,73,94–97]

Mitochondria), IP3R (MAM), Insig (ER)

HIV PDGFR (PM) [37,98–103]

Huntington's disease (HD) BiP (ER), D2R (PM), Emerin (NE) [69,104–107]

Pain/spinal cord injury MOR (PM), NR1 (PM), CB1R (PM), TrKB (PM) [25–27,108–122]

Parkinson's disease (PD) TrkB (PM), Emerin (NE), IP3R (MAM), Insig (ER) [70,123,124]

Psychiatric disorders BiP (ER), TrkB (PM), IP3R (MAM) [36,125–136]

(schizophrenia and depression)

Stroke and ischemia BiP (ER), IP3R (MAM) [123,137–140]

Traumatic brain injury (TBI) BiP (ER), IP3R (MAM) [141]

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associates and modulates the downstream signaling of D1R and D2R when neurons are
stimulated by cocaine.

Muscarinic Acetylcholine Receptor (mAchR)

mAchRs are G-protein-coupled receptors (GPCRs) for acetylcholine that have important roles in
the control of motor neurons in the brain.

In a ventral horn motoneuron model, Mavlyutov et al. [21] examined the distributions of Sig-1Rs
at the synaptic contact site. Immunoelectron microscopy revealed that Sig-1Rs are located in
the postsynaptic densities and are juxtapositional to the metabotropic mAchR M2. Visualization
of the ultrastructure of Sig-1Rs indicated that they are excluded from the PM and instead are
primarily located in the subsurface ER cisternae. Since the interaction between Sig-1R and
mAchRM2 may promote the survival or proper functioning of motor neurons, their close
proximity suggests a role of Sig-1R in amyotrophic lateral sclerosis (ALS), whose hallmark is
motor neuron degeneration.

Mu-Opioid Receptor
MOR is an opioid receptor subtype that mediates morphine-induced analgesia. Although Sig-1R
is not an opioid receptor subtype (see above), numerous studies have focused on endogenous
Sig-1R as a negative modulator of opioid analgesia [22–26]. As such, Sig-1R antagonists would
potentiate morphine-induced analgesia. The functional and physical association of Sig-1R with
MOR was recently assessed by guanosine 50 -O-(3-[35S]thio)triphosphate ([35S]GTPgS) binding
and by coimmunoprecipitation experiments using epitope-tagged receptors [27]. Interestingly,
this study also showed that, in mouse brain membrane preparations, Sig-1R-selective antag-
onists could potentiate both opioid receptor and mAchR-mediated stimulation of [(35)S]GTPgS
binding. These results suggest a broader role for Sig-1Rs in modulating GPCR signaling [27].

Sig-1R also has been demonstrated to modulate opioid analgesia through its interaction with the
NMDA receptor NR1 subunit (GluN1) [28] (see next section). The potential role of Sig-1R in the
crossregulation between MOR and NMDARs was demonstrated by using peptide interference
assays and immunohistochemistry in mouse mesencephalic periaqueductal gray matter. These
results suggest that the Sig-1R–MOR–GluN1 trimeric complex has a role in nociception.
However, further investigation is needed to clarify the relation between the trimeric complex
and MOR-induced analgesia.

NMDAR and Cannabinoid Receptor 1 (CB1R)

The NMDA receptor is an ion channel type of receptor for glutamate and comprises a hetero-
tetramer between two GluN1 and two GluN2 subunits. NMDAR controls various neuronal
functions, including synaptic plasticity and memory. CB1R is a GPCR for endocannabinoids
such as anandamide and 2-arachidonoylglycerol, and is expressed at presynaptic neurons,
where it modulates the release of the neurotransmitter glutamate.

Sig-1R has been extensively studied in cognitive function, particularly in psychiatric disorders.
Sig-1R agonists have been shown to enhance NMDAR functionality [29,30]. Combining AFM
studies and in situ proximity ligation assays, Balasuriya et al. [31] demonstrated a direct
interaction between Sig-1R and NMDAR. Sig-1R bound directly to the NMDAR subunits
(GluN1/GluN2A heterotetramers) specifically via interaction with the GluN1 subunit. Interestingly,
Sig-1R agonist administration resulted in the upregulation of GluN2A and GluN2B expression in
the synaptosomal fraction [32]. The Sig-1R antagonist abolished the agonist-induced increase
of synaptosomal expression of GluN2A and GluN2B and their associated trafficking to the PM.
Coimmunoprecipitation studies also revealed increased interaction between Sig-1Rs and GluN2
subunits in response to a Sig-1R agonist [32]. A recent study suggested that Sig-1R functions as

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a safety switch to control CB1–NMDAR interactions to prevent CB1R-provoked NMDAR

hypofunction [33]. Interactions of Sig-1Rs with CB1R, GluN1, and the histidine triad nucleo-
tide-binding protein 1 (HINT1) were visualized by bimolecular fluorescence complementation
assays. These data suggested that the assembly of the CB1–HINT1–GluN1 protein complex is
critically regulated by Sig-1R. These findings indicate that Sig-1R regulates synaptic plasticity,
perhaps via dynamic protein associations. The main function of Sig-1R in this regard is
suggested to restore the hypofunctional NMDAR that resulted from interactions with CB1R.
The authors proposed that this action of Sig-1R regulates the balance between the opposing
effects of CB1R and NMDAR in the context of analgesia and certain psychiatric disorders, such
as schizophrenia; indeed, hypofunctional NMDAR has been implicated in this disease.

Tropomyosin Receptor Kinase B (TrkB)

TrkB is a cell surface tyrosine kinase receptor for brain-derived neurotrophic factor (BDNF) and
neurotrophin 4. It has important roles in the brain, including synaptic transmission, neurogenesis,
learning, and cognition.

Sig-1R agonists exert antidepressant-like effects and neuroprotective effects via the upregu-
lation [34] or enhanced post-translational processing [35] of BDNF. In addition, Kimura et al. [36]
reported that Sig-1R interacts with TrkB in cerebellar granule neurons and promotes neurite
elongation. The authors also demonstrated that coimmunoprecipitation of Sig-1R and TrkB was
strengthened by the Sig-1R agonist PRE-084.

Platelet-Derived Growth Factor Receptor (PDGFR)

PDGFR is cell surface tyrosine kinase receptor for PDGF and has a role in the regulation of cell
proliferation, cellular differentiation, cell growth, and development; it is also thought to have a role
in many diseases, including cancer.

It is known that the HIV-associated increase in monocyte adhesion and trafficking is exacer-
bated by cocaine abuse. One of the underlying mechanisms involves cocaine-mediated
upregulation of cell adhesion molecules that results in subsequent disruption of the blood–
brain barrier (BBB). PDGFR is known to cause the transcriptional increase of an adhesion
molecule called ALCAM by activating the transcription factor nuclear factor (NF)-kB. However,
the exact relation between the HIV-related action of cocaine and PDGFR was unclear until a
study by Yao et al. [37].

Yao et al. showed that, in human brain microvascular endothelial cells, Sig-1R can interact with
PDGFR and that this interaction was intensified as a result of cocaine causing the translocation of
Sig-1R from the MAM to the PM [37]. This interaction of Sig-1R with PDGFR enables cocaine to
enhance the transmigration or infiltration of leukocytes across the BBB by increasing the
expression of ALCAM. Furthermore, because NF-kB also mediates inflammation, the Sig-
1R–PDGFR interaction has an important role in HIV-induced inflammation, which is also known
to be exacerbated by cocaine.

Integrin-b1
Integrins are transmembrane receptors for cell adhesion molecules, including fibronectin and
collagen, and are important for the metastasis of cancer cells. Integrin is a heterodimer
comprising / and b subunits.

Sig-1R has been reported to interact with integrin-b1, which facilitates cell adhesion [38].
Interestingly, this interaction was blocked by the Sig-1R ligand SKF-10047, which is a Sig-
1R agonist. Furthermore, the silencing of Sig-1Rs by siSig-1R attenuated cell adhesion. These
two seemingly contradictory results require further clarification. Nevertheless, the interaction

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between Sig-1R and integrin-b1 suggests a role for Sig-1R in cell adhesion and perhaps the
progression of cancer cells.

Voltage-Gated Potassium Channels (Kv)

Kvs occur on the PM and have an important role in returning the depolarized cell to a resting state
during action potentials.

By reconstituting responses seen in Xenopus oocytes, two separate groups showed that Sig-
1Rs regulate Kv1.3 and Kv1.4. Aydar and colleagues [39] demonstrated a functional interaction
between Sig-1R and Kv1.4 in the absence of ligands. A decade later, Kinoshita et al. [40]
revealed that Sig-1R interacts at the transmembrane domain of Kv1.3 channels and alters their
kinetics. In contrast to the study by Aydar et al., Kinoshita and colleagues claimed that Sig-1R
ligands are not required to alter (or block) the interactions between Kv1.3 channels and Sig-1R.
The interactions and dynamics of Sig-1R with Kv1.2 were later identified and established in an
animal model. In this report, cocaine exposure induced Sig-1R translocation to the PM and
shaped intrinsic plasticity via the persistent association of Sig-1R and Kv1.2 in the nucleus
accumbens shell medium spiny neuron [41]. Additionally, a recent study using confocal imaging
revealed the colocalization of Sig-1R and the Kv2.1 channel in the C terminals of motor neurons
[21]. The relation between Sig-1R and other ion channels was extended to a cardiac Kv human
either-à-gogo related gene (hERG). The study was carried out in the leukemic K562 cell line and
explored potential pharmacological targets to reduce cancer progression. Electrophysiological
data showed that Sig-1R modulated the hERG current density in the presence of ligands [42].
Biochemical approaches, including the coimmunoprecipitation studies, suggested that Sig-1R
expression potentiates the ER–Golgi translocation and maturation of the hERG subunit [42].
AFM and homogenous time-resolved fluorescence approaches later showed that Sig-1R
interacts with hERG with a fourfold symmetry. The authors confirmed that the direct interaction
between Sig-1R and hERG in the PM is not Sig-1R ligand dependent but is reduced by
cholesterol depletion, suggesting that Sig-1R binds to hERG in the ER and facilitates hERG
assembly and trafficking, perhaps in a lipid raft-related fashion [43]. The interaction of Sig-1R
with hERG in the ER and in potentiating hERG maturation and translocation to the PM suggests
that Sig-1R has chaperoning activities in the ER to facilitate proper protein sorting to their final
destinations. Thus, this relation between Sig-1R and hERG may also apply to other Sig-1R-
interacting partners.

Voltage-Gated Sodium Channels (Nav)

Nav on the PM are responsible for action potential initiation and propagation in excitable cells
including nerve, muscle, and neuroendocrine cells.

Sig-1R has been reported to modulate several sodium channels, including Nav1.2, Nav1.4, and
Nav1.5 [44–46]. These studies investigated the modulation of Nav by Sig-1R by using various
Sig-1R ligands. Results indicated that Sig-1R agonists exerted inhibitory action on the Na+
current that was in turn blocked by the Sig-1R antagonist progesterone [47]. AFM imaging of the
co-isolated Sig-1R and Nav1.5 demonstrated that Sig-1R binds to Nav1.5 with a fourfold
symmetry [44].

Notes on the Interaction of Sig-1R with Proteins at the Plasma Membrane

Increasing reports are adding to the list of ER Sig-1R chaperone-associated partners. While
most findings are based on the assumption that Sig-1R forms physical interactions with these
proteins and regulates their activities at the PM, immunoprecipitation and the subsequent
western blotting of endogenous Sig-1Rs remains technically challenging due to the lack of a
high-affinity Sig-1R antibody as well as interfering signals from the control IgG, which has the
same molecular weight as Sig-1R. Thus, most studies were carried out in an overexpression

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system, in which Sig-1Rs are expressed together with tagged proteins and, thus, are usually
oversaturated in the cellular compartments, which may lead to aberrant protein localizations.
Therefore, it is conceivable that overexpressed tagged Sig-1Rs may associate with some
proteins that endogenous Sig-1R may not. Furthermore, the electron microscopy study by
Mavlyutov and coworkers demonstrated that Sig-1R could be localized in the proximity of the
PM. Thus, Sig-1R may interact with PM proteins via its proximity to the PM. Finally, a recent
report suggested that Sig-1R activation inhibits store-operated Ca2+ (SOCE) entry effects in rat
brain microvascular endothelial cells [48]. However, the physical interaction, if any, between Sig-
1R and the SOCE protein complex ORAI1 or STIM1 has yet to be established.

In the Cytosol
Cell Engulfment and Motility Domain (ELMOD)
ELMOD proteins are GTPase-activating proteins (GAPs) for the ADP Ribosylation Factors (ARFs)
and ARF-likes (ARLs) and can bind to the activated form of the GTPase (e.g., GTP-ARFs) to
speed up the rate of hydrolysis of GTP and, consequently, inactivate the associated signaling.

Distinct GTPases control a variety of crosstalk signaling pathways, which require specific
regulators, guanine-nucleotide exchange factors (GEFs), and GAPs. Those GTPases coupled
with, and controlled by, GEFs or GAPs can be activated or inhibited, respectively, depending on
their roles in the signaling pathway. Thus, investigation of the specificities and binding partners
of GEFs and GAPs is essential for the construction of integrated models of cell signaling.
Ivanova et al. [49] reported that ELMOD proteins are GAPs for the ARF family with links to
deafness. According to their results, Sig-1R acts as a new effector of the GAP activity of
ELMOD1–3 proteins because direct binding of Sig-1R to either ELMOD1 or ELMOD2 resulted
in the loss of GAP activity. This observation opens up a new link between Sig-1R and GTPase
(see below).

Ras-Related C3 Botulinum Toxin Substrate (Rac)-GTPase

Rac-GTPase represents a subfamily of the Ras homolog gene (Rho) family of GTPases and is
known to regulate tumor cell migration, dendritic growth, and dendritic spine maturation.

Tsai et al. discovered that Sig-1R regulates neuritogenesis and spine maturation via a signaling
pathway involving Rac1-GTPase and its regulator TIAM1 [50]. Recently, by using immunopre-
cipitation, Natsvlishvili et al. [51] reported that Sig-1R not only interacts directly with Rac1-
GTPase, but also forms complexes with inositol 1,4,5- trisphosphate receptor type 3 (IP3R),
binding immunoglobulin protein (BiP), and Bcl2 in the brain mitochondria. Interestingly, the
ligand-specific assembly complex relies on the Sig-1R agonist/antagonist and the presence of
GTP/GDP. The authors concluded that the Sig-1R-induced Rac1 signaling would trigger mild
oxidative stress, which would impact neuroplasticity as well as preventing apoptosis and
autophagy.

At the ER–Mitochondrion Interface and Mitochondria

Binding Immunoglobulin Protein
BiP, also known as 78-kDa glucose-regulated protein or heat shock 70-kDa protein 5, is a
constitutively expressed ER protein that functions as a molecular chaperone. Bip is involved in
the folding, translocation, and assembly of proteins. It was reported that Sig-1R forms Ca2
+
-sensitive chaperone machinery with BiP under normal physiological conditions [7,52]. How-
ever, the lowering of the local Ca2+ concentration, such as by the efflux of Ca2+ from IP3R,
causes Sig-1R to dissociate from BiP. Furthermore, independent of the effect of local Ca2+, Sig-
1R agonists, such as cocaine or (+)pentazocine, can also cause the dissociation of Sig-1R from
BiP [7,13]. It is known that this causes Sig-1R to translocate from the MAM to the PM and
nucleus.

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Inositol 1,4,5- Trisphosphate Receptor Type 3 and Ankyrin

In general, IP3R has an important role in the generation, propagation, and regulation of
cytoplasmic Ca2+ signals that regulate numerous physiological and pathophysiological pro-
cesses. IP3R3, a subtype of IP3R, localizes mainly at the MAM and, when activated by its
agonist IP3, allows Ca2+ to efflux from the ER into mitochondria. However, after allowing for the
Ca2+ efflux, the conformation of IP3R3 is altered and it subjected to proteasomal degradation.
The degradation of IP3R3 puzzled researchers for many years: how does a cell restore the
conformation of IP3R3 to ensure correct Ca2+ signaling from the ER into mitochondria? The
answer is provided by the discovery of Sig-1R.

After dissociating from BiP, Sig-1R begins to bind to, and chaperone, IP3R3 at the MAM [7]. As
such, Sig-1R ensures proper Ca2+ efflux from the ER into mitochondria via IP3R3 at the MAM
and sustains and/or enhances cellular survival. Interestingly, it was demonstrated by Boehning
et al. [8] that cytochrome c can bind IP3R3 and regulate Ca2+ signaling. Therefore, the possibility
exists that the trimeric complex of Sig-1R–IP3R3–cytochrome c may have an important role in
the homeostatic regulation of ER–mitochondrion Ca2+ signaling.

Ankyrins, a family of cytoskeletal adaptor proteins, have been known to inhibit Ca2+ efflux from
intracellular organelles by interacting with IP3Rs at the ER [53]. It was demonstrated that Sig-1R
agonists cause the dissociation of ankyrins from the IP3R to open up the IP3R for Ca2+ efflux
from the ER into the cytosol [54]. However, the exact relation among Sig-1R, BiP, ankyrins, and
IP3R remains to be totally clarified.

Voltage-dependent Anion Channels (VDAC)

VDAC localize at the outer mitochondrial membrane (OMM) and form a complex with IP3R that
resides at the ER. The VDAC–IP3R complex facilitates the transfer of Ca2+ from the ER to
mitochondria.

Marriott et al. [55] reported that Sig-1R can interact with VDAC and contributes to the regulation
of mitochondrial pregnenolone synthesis. Studies have shown that VDAC on the OMM may
interact with steroidogenic acute regulatory protein [56], another exclusive OMM protein, and
enhances cholesterol import. Marriott et al. also revealed that deletion of Sig-1R disrupted the
bridge formed via the association of Sig-1R with VDAC2, resulting in inhibition of cholesterol
influx into the mitochondria. This Sig-1R–VDAC interaction may have an even more important
role in ER–mitochondrion crosstalk that has yet to clarified. Furthermore, it may be that this Sig-
1R–VDAC interaction is partly responsible for maintaining the integrity of the MAM. In fact, losing
MAM integrity by Sig-1R knockdown has been speculated to be involved in the development of
Alzheimer's disease (AD) [57].

Inositol-Requiring Enzyme 1 (IRE1)

IRE1 is an ER stress sensor that can splice the mRNA of X-box binding protein 1 (XBP1) to allow
for expression of the functionally active transcription factor XBP1, which in turn translocates into
the nucleus to induce the upregulation of several ER chaperones and antioxidant proteins or
enzymes.

The ER provides an exclusive environment for protein synthesis and folding, which is vital to
cellular function. Under normal conditions, there is a balance between the synthesis and
degradation of proteins. Yet, numerous external insults can affect this balance, causing the
accumulation of undegraded or misfolded proteins. Thus, cells rely on a system, the unfolded
protein response, which regulates the homeostasis of the ER by signaling the protein-handling
problem to the nucleus via three ER stress sensors: IRE1, PERK, and ATF6. Mori et al. reported
[10] that IRE1, but not PERK or ATF6, resides mainly at the MAM and that mitochondria-derived

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ROS can preferentially activate IRE1 at the MAM. Furthermore, Sig-1R interacts only with IRE1
and not PERK or ATF6. Thus, Sig-1R can stabilize IRE1 to ensure a proper mitochondrion–ER–
nucleus signaling axis for cellular survival by prolonging the activation of the IRE1–XBP1 signaling
pathway.

Insulin-Induced Gene (Insig)

Insig is an ER protein that has an important role in the ER control of cholesterol and lipid
homeostasis by affecting the degradation of lipid-synthesizing enzymes via the ER-associated
degradation system (ERAD).

Sig-1R has a key role in oligodendrocyte differentiation by facilitating degradation of the enzyme
ceramide galactosyl transferase (CGalT), which synthesizes galactosylceramide to negatively
affect oligodendrocyte differentiation [58]. Sig-1R does this by forming a complex with Insig at
the ER that is part of the ERAD that degrades the CGalT enzyme [58]. Sig-1R agonists promote
the formation of the Sig-1R–Insig complex to increase the degradation of CGalT and reduce the
production of the negative regulator galactosylceramide. This study suggested that Sig-1R is an
important member of the ERAD system.

At the Nuclear Envelope: Emerin

The nuclear envelope comprises the outer and inner nuclear membranes. It is a highly organized
dynamic barrier that separates the nucleus from the cytosol. The ER and nuclear envelope form a
continuous network since both the inner and outer nuclear membranes are contiguous lipids
from the rough ER membrane. Dussossoy et al. [59] first reported the colocalization of Sig-1R
and sterol isomerase at the nuclear envelope and the ER. In Sig-1R-EYFP-overexpressing
NG108 cells, Sig-1R agonists caused Sig-1R to translocate toward the nuclear envelope and
the tip of the neurite [60]. Recently, an electron microscopy study revealed the precise
subcellular distribution of Sig-1R in retinal neurons [14]. This study confirmed that Sig-1Rs
are localized in the inner and outer membrane of the nuclear envelope. These observations led to
the important discovery that Sig-1R is a transcriptional regulator at the nuclear envelope. Tsai
et al. [15] discovered that Sig-1R translocates from the ER to the outer nuclear membrane and
interacts with the inner nuclear membrane protein emerin and likely the nuclear pore complex
protein Ran-binding protein2 (RanBP2). Confocal imaging and coimmunostaining studies
demonstrated the interaction of Sig-1R and emerin at the nuclear envelope and the subsequent
recruitment of barrier-to-autointegration factor, histone deacetylase 2, and the specific tran-
scription factor 3 to the promoter of the monoamine oxidase B (MAOB), which suppressed the
gene transcription of MAOB. Cocaine acts as an Sig-1R agonist to intensify the complex
formation. This finding opens a new chapter on how cocaine or other drugs may change
the drug reward system. It is a widely accepted concept that cocaine and other drugs, such as
methamphetamine, alter the dopamine (DA) levels in the synaptic cleft by blocking DA reuptake
and hijacking the brain reward system. This latest report demonstrating that cocaine, via Sig-1R,
is able to reduce the MAOB level in the nucleus accumbens in a DA transporter-independent
manner provides a new mechanism to understand the complexity of addictive processes.

Sig-1R-Interacting Proteins Revealed by Bioinformatics Analyses

Proteomic and bioinformatics analyses have become important methods to predict potential
protein–protein interactions. Many bioinformatics methods have been developed using different
data-mining routes and criteria (e.g., [61–63]). For the purposes of this article, we selected the
study by Schmitt et al. [61]i to look for predicted Sig-1R-interacting proteins; this selection was
made partly because the confidence level of each predicted protein was easily accessed
(Figure 2). We arbitrarily chose a confidence level of 0.948 for potential candidates because
one of the nuclear proteins of interest was at this confidence level. The predicted Sig-1R-
interacting proteins in humans are detailed in Figure 2.

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The information from bioinformatics provides insights into the potential proteins that theoretically
could interact with Sig-1R. However, more experimental evidence is needed to validate these
results. For example, only two (HSPA5/BiP and VDAC2) of the 22 Sig-1R-interacting proteins
detailed in Figure 1 were correctly predicted by bioinformatics to be high-potential interactors at
a confidence level of 0.948. The other 19 proteins were not predicted to be potential interactors,
even at a confidence level of 0.30, except for the mouse Rac1, which has a confidence level of
0.302. In addition a predicted high-potential interactor (lamin B receptor; LBR) did not coim-
munoprecipitate with Sig-1R under experimental conditions [64], whereas a low-potential
protein with a confidence level less than 0.30 (lamin A receptor), was shown to coimmuno-
precipitate with Sig-1R [64]. This pattern of discordance between experimental results and
bioinformatic predictions applies to those in human, mouse, and rat. Similar patterns of
discordance were also found when searching potential Sig-1R interactors using tools from
other two reports [62,63].

The above discordance notwithstanding, these predicted Sig-1R interactors may be indirect
‘functional interactors’ rather than direct physical interactors. Furthermore, many of the high-
potential interactors based on the bioinformatic predictions have not yet been tested in
coimmunoprecipitation or other proximity assessment assays. Thus, the discordance discussed
above may be reconciled in future studies.

CNS Diseases Associated with Sig-1R: Speculation on the Role of Sig-1R in

Complex with its Protein Partners
Sig-1R has been reported to be involved with several CNS diseases (Table 1). Although the exact
Sig-1R-interacting protein(s) that may relate to each disease are not yet fully clear, we have
tentatively placed them in Table 1 simply to indicate their possible role, and speculate further on
their involvement in CNS diseases below.

Amyotrophic Lateral Sclerosis (Lou Gehrig's Disease)

In animal models, the loss of function of Sig-1Rs in motor neurons disrupts ER–mitochondrion
contact, reducing Ca2+ signaling and stunted axon extension, leading to ALS [65]. Thus, the
action of Sig-1R–IP3R–VDAC in maintaining an intact contact between ER and mitochondria
may have an important role in this disease. Furthermore, the close proximity of Sig-1R to the
mAChR at the PM [21] may also be significant in this disease. In addition, the Sig-1R–Insig
interaction may participate in the etiology of ALS because Insig was reported to reduce
glutamate-induced excitotoxicity, a feature of this disease [66].

Alzheimers’ Disease
Sig-1R has an important role in maintaining the structural integrity of the MAM through the
tethering of Sig-1R with IP3R and VDAC. ER–mitochondrion crosstalk that occurs via the Sig-
1R–IP3R–VDAC linkage at the MAM has recently been implicated to have an important role in the
pathogenesis of AD [57]. Knockdown of Sig-1R causes neurodegeneration and the level of Sig-
1Rs is reduced in the brain of patients with AD [57]. In addition, the Sig-1R–Insig interaction may
also have a role in this disease because Insig has been shown to affect cholesterol synthesis
during the progress of AD [67].

Huntington's Disease
The ‘dopamine system stabilizer’ class of drugs [68] has been suggested as potential agents to
treat Huntington's disease (HD) because such drugs can act either as functional agonists or a
functional antagonists depending on the initial levels of DA. One such drug is 4-[3-(methyl-
sulfonyl)phenyl]-1-propylpiperidine (pridopidine). Pridopidine, in addition to binding to D2R,
bound Sig-1R with an affinity 20 times higher than that at D2R in a PET imaging study [69],
suggesting that it works through its duel actions at D2R and Sig-1R [69]. Given that Sig-1R has

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 TIPS 1304 No. of Pages 17

been shown to interact directly with D2R [20], it is tempting to speculate that the Sig-1R–D2R Outstanding Questions
interaction has an important role in the action of pridopidine. The positive effect of pridopidine What is the structural basis that ena-
against the progress of HD may involve the ability of the drug, as seen with cocaine [15], to bles Sig-1R to interact with so many
different classes of proteins with
translocate Sig-1Rs to the nuclear envelope to recruit chromatin-remodeling factors, which then diverse structure and functions?
suppress gene expression of MAOB, thus increasing DA levels in the brain. However, this
possibility requires further testing. Why would such a protein have evolved
in living systems?

Pain or Neuropathic Pain Is Sig-1R the only protein with unique

Sig-1R per se or its agonists have been demonstrated to be involved in the attenuation of pluripotent actions?
morphine-induced analgesia [25–27]. These results suggest Sig-1R to be an endogenous pain
Are all of the actions of Sig-1R described
modulator in the CNS. Although the exact molecular mechanism remains to be clarified, Sig-1R
here related to its chaperone nature, or
was shown to coimmunoprecipitate with MOR in HEK cells [27]. Furthermore, as stated above, are there yet to be discovered other
Sig-1R also coimmunoprecipitates with the NMDA receptor subunit GluN2 [32] as well as with explanations for its actions?
CB1R [33], both of which are known to be involved in pain perception. Thus, Sig-1R antagonists
Given that Sig-1R can interact with so
combined with morphine are being developed as analgesic agents enabling practitioners to
many functional proteins in living sys-
reduce the dose of morphine while still maintaining effective analgesia. tems, how can drugs be designed to
target the specific disease-related pro-
Parkinson's Disease teins with which Sig-1R interacts, with-
out affecting other interacting proteins?
A Sig-1R agonist PRE-084 was found to induce functional neurorestoration in experimental
Parkinsonism in that density of dopaminergic fibers was increased and a modest recovery of DA
level was seen [70]. Furthermore, this agonist treatment also caused a wider intracellular
distribution of Sig-1Rs [70], due to agonist-induced Sig-1R translocation. Although the Sig-
1R-interacting partner protein was not identified in this report, it is tempting to speculate that the
Sig-1R agonist PRE-084 may cause the translocation of Sig-1Rs to the nuclear envelope, where
they bind emerin, which in turn recruits chromatin-remodeling factors to suppress gene
expression of MAOB [64], thus reducing DA degradation and causing an increase of DA in
the brain. However, another possibility for the involvement of Sig-1R in this disease is that it can
interact directly with TrkB [36] to enhance the receptor binding and/or signaling of BDNF, which
is known to promote the survival of neurons.

Depression
The neurotrophic factor BDNF has an important role in combating depression because it causes
increases in dendritic spines and axon elongation for enhanced communication between
neurons [71,72]. BDNF does so via its receptor TrkB at the PM. Sig-1R has been shown to
be involved in depression partly through its action in stabilizing the post-translational processing
of mature BDNF [35]. Interestingly, Sig-1R was also shown to coimmunoprecipitate with TrkB
[36], suggesting that one of the antidepressive actions of Sig-1R may be due to its ability to bind
TrkB, thereby enhancing signaling downstream of this receptor.

Cocaine Addiction
The Sig-1R–Kv1.2 interaction has been shown to shape neuronal and behavioral responses to
cocaine [41]. This study showed that cocaine ‘hijacks’ Sig-1R to increase the interaction
between Sig-1R and Kv1.2 to decrease the intrinsic excitability of GABAergic neurons, thus
leading to cocaine-induced behavioral sensitization. In addition, cocaine also causes the
translocation of Sig-1R from the ER to the nuclear envelope to interact with emerin, which
suppresses the gene transcription of the DA-metabolizing enzyme MAOB; this facilitates the
action of cocaine [64].

Concluding Remarks
Thus, because Sig-1R represents a new type of functional protein in living systems, in that it can
bind and modulate many different classes of functional proteins in many parts of the cell, we
suggest that it should be called a pluripotent modulator (see Outstanding Questions). It is

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 TIPS 1304 No. of Pages 17

perhaps because of this unique action that the receptor is involved in affecting or regulating so
many different physiological and pathological conditions.

At the MAM, the interaction between Sig-1R and other proteins encompasses functional
sequelae for cellular survival because Sig-1R: (i) chaperones client proteins to maintain proper
Ca2+ signaling from ER into mitochondria to ensure mitochondrial ATP production for bioener-
getics; (ii) attenuates free radical generation by ensuring proper mitochondrion–ER–nucleus
signaling; (iii) maintains the structural integrity of the contact between ER and mitochondria to
facilitate the functional crosstalk of these two critical organelles; (iv) serves as a member of ERAD
to regulate homeostasis of functional proteins; and (v) serves as the carrier of signaling lipids,
specifically myristic acid [73], for proper neuron functionality. Outside of the MAM, the functional
sequelae of the Sig-1R–target protein interaction may not be involved in cellular survival but in
general relates to positive or negative modulation of the function of the target protein.

Although we have speculated here on the potential role of the Sig-1R–target protein interaction in
certain CNS diseases, significant questions remain, including: (i) what is the molecular basis of
signaling that may relate the disease, in particular neurodegenerative diseases, to Sig-1R at the
MAM? If a functionally aberrant protein causes a disease, how does the cell signal the aberrance
of that protein to Sig-1R at the MAM? (ii) If the disease causes Sig-1R to translocate from the
MAM, does Sig-1R translocate to all other parts of the cell where it has been described? (iii) Does
Sig-1R affect only dysfunctional proteins? Does Sig-1R have any effect on functionally normal
proteins? And (iv) Does Sig-1R regulate the function of its interacting protein partner only by
chaperoning the conformation of that partner or by other as yet unknown actions?

Several questions also remain concerning Sig-1R-related therapeutic agents for disease treat-
ment: (i) Sig-1R agonists that may be effective in treating certain neurodegenerative diseases
may also cause Sig-1R to translocate from the MAM. What would the consequence be in terms
of treatment efficacy? (ii) Does the Sig-1R agonist continue to bind Sig-1R after causing the
translocation of Sig-1R from the MAM? (iii) What is the action of the Sig-1R agonist if it is
translocated together with Sig-1R to, for example, the PM? Does the agonist serve to enhance
the chaperone activity or other as yet unknown activities of Sig-1R at the destined location? (4)
Can the Sig-1R antagonist block the action of Sig-1R even after Sig-1R forms a complex with
target protein at the PM or nuclear envelope? And, (v) In the case of hERG, to which Sig-1R binds
at the ER and then co-translocates to the PM, how do we design drugs to facilitate or break up
the interaction at the desired loci in a cell?

It is still unknown why Sig-1R can interact with so many structurally diverse proteins. Although
numbers of chaperone proteins in the living system are limited, those chaperones have to maintain
or help degrade thousands of other proteins. Thus, it is understandable that a chaperone has to
interact with, and assist, many client proteins, as is the case for Sig-1R. However, Sig-1R differs
from other chaperones in that it has two transmembrane regions, whereas these are lacking, as far
as we know, in all other chaperones. A particularly interesting question concerning the two
transmembrane regions of Sig-1R is whether they have any unique role in the action of Sig-1R
as a chaperone. This is an important question to address given that most Sig-1R-interacting
proteins are also transmembrane proteins. In addition, Sig-1R differs from other chaperones in that,
while most of the actions of chaperones with their target proteins require ATP, those of Sig-1R do
not [7]. Finally, it has to be mentioned that, although we do not understand as yet the overall
underlying mechanism, there is specificity in the Sig-1R binding with its partners. For example, while
Sig-1R binds Kv1.2, it does not bind Kv4.2 [41]. Similarly, Sig-1R binds IP3R3 but not IP3R1 [7].

Recent publications reporting the existence of Sig-1Rs in equilibrium as monomers, dimers, and
higher oligomeric forms may provide some answers, at least in part, as to why Sig-1Rs bind so

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 TIPS 1304 No. of Pages 17

many target proteins or even ligands [13,74,75]. The formation of oligomers does not involve
disulfide bonds. Sig-1R agonists appear to favor monomers and dimers, while antagonists favor
oligomers. Interestingly, certain ligands have been found to abolish the monomeric Sig-1R
interactions with the PM ion channels. Thus, the ligand-gated oligomer–monomer equilibrium
state of Sig-1Rs could result from the fact that these receptors are able to bind many different
classes of ligands, target diverse proteins, and exert different chaperoning activities [13,74,75].

Whether Sig-1R is the only member of this new ‘pluripotent modulator’ class of protein remains
to be clarified. Also unknown is the exact relation between the ligand-induced oligomerization of
Sig-1Rs and all of the actions of Sig-1Rs described above, including these in disease states.
More investigations are certainly warranted to advance our understanding of this unique
pluripotent modulator protein. Lastly, although Sig-2R has not been cloned, it is not unrea-
sonable to speculate that it could also be a chaperone, albeit with potentially different
interacting partners from those of Sig-1R. This speculation is based on many studies that
have reported close and overlapping pharmacological and biochemical properties between
Sig-1R and Sig-2R.

Acknowledgments
This work is supported by the Intramural Research Program of the National Institute on Drug Abuse. T-C.S. is supported, in
part, by the Dragon Gate Program of the Ministry of Science and Technology of Taiwan (MOST #105-2911-I-038 -503). Y.
N. is supported in part by the Japanese Society for Promotion of Sciences.

Resources
i
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