Sigma 1 Receptor and Its Pivotal Role in Neurological Disorders

Abstract

Sigma 1 receptor (S1R) is a multifunctional, ligand-activated protein located in the membranes of the endoplasmic reticulum (ER). It mediates a variety of neurological disorders, including epilepsy, amyotrophic lateral sclerosis, Alzheimer’s disease, Huntington’s disease. The wide neuroprotective effects of S1R agonists are achieved by a variety of pro-survival and antiapoptotic S1R-mediated signaling functions. Nonetheless, relatively little is known about the specific molecular mechanisms underlying S1R activity. Many studies on S1R protein have highlighted the importance of maintaining normal cellular homeostasis through its control of calcium and lipid exchange between the ER and mitochondria, ER-stress response, and many other mechanisms. In this review, we will discuss S1R different cellular localization and explain S1R-associated biological activity, such as its localization in the ER-plasma membrane and Mitochondrion-Associated ER Membrane interfaces. While outlining the cellular mechanisms and important binding partners involved in these processes, we also explained how the dysregulation of these pathways contributes to neurodegenerative disorders.

Sigma receptors (S1Rs) have a great interest as possible therapeutic targets for many various neurological diseases.¹⁻³ In 1996, the S1Rs were cloned and characterized as a protein consisting of 223 amino acids with a one transmembrane domains,⁴ later they were proved to have two transmembrane domains.⁵ They were considered unique receptors, as they were shown to have distinct binding sites from those of the opioid receptors with at least two subtypes (type 1 and type 2).⁶ Several psychotropic drugs show moderate to high affinity for S1R, including antidepressants, antipsychotics, psychostimulant, and anticonvulsants.⁷ In addition, several neurosteroidal medications have been revealed as the ligands of S1R and are known to interact with these receptors.⁸ As a consequence of their extensive modulatory effect, S1R ligands have been reported to be helpful in a variety of neurotherapeutic applications.^3,6

Structure, Localization, and Distribution of S1Rs

As a result of the specific character of the S1R as endoplasmic reticulum (ER)-resident protein, it helps them to function as chaperone proteins and intracellular receptors.^9,10 They are highly expressed in neurons, glial cells of astrocytes, hippocampus, hypothalamus, mesencephalon, and olfactory bulb in the central nervous system (CNS).¹¹ However, these receptors are also located in the endocrine, immunological, and reproductive systems, as well as the liver, kidney, lungs, muscles, urinary bladder, and bones.¹²

S1Rs are single 223 amino acid polypeptides (26 kDa) with a trimeric architecture of the protomers in the crystal structure that was revealed to include two transmembrane domains per protomer¹³ [Figure 1].

Figure 1.

A graph showing the structure of S1R. S1R consists of a total 223 amino acid polypeptide.

The ligand-binding site was hidden in the middle of a cupin-like barrel that was part of the carboxy-terminal domain.¹⁴ As chaperone proteins, S1R do not have their own intrinsic signaling machinery. Instead, upon ligand activation, they appear to operate primarily via translocation and protein–protein interactions to modulate the activity of various ion channels and signaling molecules, including inositol phosphates, protein kinases, and calcium channels.¹⁵ The S1R have been identified in extremely tiny portions in the postsynaptic thickenings of the neuron’s ER/mitochondrial associated membranes (MAM).¹⁶ At the MAM, they are sequestered with glucose-related protein 78- binding immunoglobulin protein (BiP), a major ER chaperone protein.¹⁷ Following activation, the receptors detach from BiP and modulate calcium signaling either inside the MAM or by translocating to the plasma membrane.¹⁷ S1R translocate to the nucleus membrane, leading to interactions of such receptor types with multiple nuclear factors as well as the management of gene transcription.^9,18

S1R was initially identified as a type 1 transmembrane protein that possessed a single transmembrane domain.⁴ Although a single-pass transmembrane topology of S1R was confirmed by hydrophobicity analysis,¹⁹ a two transmembrane domain model of S1R topology was suggested by later research.⁵ Aydar and associates, for instance, suggested two transmembrane domains (TM1 a.a. 11–29 and TM2 a.a. 80–100) based on antibody staining tests using Xenopus oocytes that expressed S1R coupled to GFP at the N- or C-terminus. They concluded that both the N- and C-termini are situated close to the plasma membrane but inside the cytoplasm since immunolabeling of the GFP-tags was not present without membrane permeabilization but was identified following permeabilization with 0.5% acetone.⁵

In contrast, S1R is positioned in ER membranes with both the N- and C-terminal sections orientated toward the ER lumen according to the topological hypothesis put forward by Hayashi and Su.¹⁷ The immunocytochemical labeling of endogenous S1R in CHO cells using antibodies that target the N- and C-termini served as the basis for this.⁵ Without permeabilization, no labeling was seen, indicating that S1R is not present in the plasma membrane. All antibodies with a distribution resembling the ER’s shape could be stained when plasma and ER membranes were permeabilized with CHAPS or Triton X-100. Only the antibody that targeted the loop domain showed staining when streptolysin-O was used to permeabilize the plasma membrane. The disparity between the topological models of Hayashi and Su (2007) and Aydar et al. (2002) might have resulted from variations in S1R localization unique to different cell types or from modified membrane insertion of GFP-fused S1R. For instance, Hayashi and Su observe that the distribution of endogenous S1R is mirrored by the fusing of YFP to the C-terminus of S1R but not the N-terminus.¹⁷

For many years, the two-pass transmembrane model was generally recognized and utilized as the structural foundation for ligand docking research and molecular modeling.²⁰ However, a single transmembrane domain structure was recently revealed by the solution of the crystal structure for human S1R. This work indicates that the protein’s C-terminal region is orientated toward the cytosolic side, whereas its short N-terminus confronts the ER lumen.²¹

Functions of S1Rs

The S1R mediates diverse signals involved in a number of different physiological and also pharmacological functions, including their ability to have a modulatory role in intracellular Ca²⁺ signaling, and G-protein coupled receptors (GPCRs).²² Further, due to the S1R position in the ER’s membrane and subcellular membranes, they have a modulatory role in the activity of a variety of neurotransmitter systems, notably in glutamatergic neurotransmission.²² Also, they impact how lipids are compartmentalized in the ER and how they are transferred to different sites inside the cell [Figure 2].²³ A crucial component of ER lipid production is the ER membranes that are connected with mitochondria, due to the fact that the physical interaction between the ER, MAM, and mitochondria is critical to the synthesis of steroids and sphingolipids.^24,25

Figure 2.

A graph representing certain interactions between S1R with ion channels and different receptors. After stimulating S1R, glucose-related protein 78 - BiP dissociates, and the S1R translocate to different sites inside the cell, interacting with different cellular components. TrkB; tropomyosin receptor kinase-B, VDAC 1, 2; voltage-dependent anion channel 1, 2.

To demonstrate the effect of S1R on lipid metabolism, it is noteworthy that the S1R has been demonstrated to bind particular sterol and sphingolipid subtypes, these lipids are essential for attracting S1R to the MAM and allowing S1R to make a protein interacting with MAM including stabilization of different receptors associated with Ca²⁺ efflux to mitochondria including inositol triphosphate protein (IP3).²⁴ It is been demonstrated that S1R knockdown reduces glucosylceramide production while increasing hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase through inhibiting ER-associated degradation.²⁶

The S1R produces a separate ER-associated degradation (ERAD) machinery, and according to a recent study, S1R regulates the degradation of several ER-localizing lipid enzymes, such as 3- HMG-CoA reductase and galactosylceramide synthase. Together with S1R, it creates a unique subclass of ERAD complexes that control protein breakdown by detecting changes in lipid concentrations at the ER membrane (such as sterol levels).²⁷

Numerous physiological functions, including autophagy, stress response, Ca²⁺ homeostasis, transcriptional activity, and cell excitability, are regulated by S1R.²⁸ Though S1R is frequently referred to as a “ligand-gated molecular chaperone,” S1R-mediated signal transduction is distinct from a classical second messenger-coupled transmembrane receptor signaling.^27,28 The idea that S1R has chaperone-like characteristics at MAMs was put forth in the groundbreaking study by Hayashi and Su in 2007.¹⁷ However, due to S1R’s lack of structural resemblance to known chaperones and numerous protein interaction surfaces, the molecular mechanism of its chaperone activity is still unknown. Based on these findings, we suggest that S1R’s biological activity in cells can be attributed to its capacity to function as an ER lipid scaffolding protein by forming cholesterol-enriched microdomains in the ER.²⁹ It was shown that S1R’s biological activity in cells can be accounted for by its capacity to function as an ER lipid scaffolding protein by forming cholesterol-enriched microdomains in the ER.²⁹

Furthermore, when the ER’s sterol concentration is high, a particular E3 ligase is sent by the complex including Insig1, to break down the lipid enzymes.³⁰ And in order to bind cholesterol at sterol-binding sites, S1R localizes to lipid rafts, which are detergent-resistant microdomains of the ER. S1R agonists, such as SKF-10047, push S1R and its binding partners out of lipid rafts, probably by out-competing cholesterol binding.³¹ Furthermore, S1R promotes myristoylation of p35, which enhances its degradation and lessens Tau hyperphosphorylation that is dependent on p25/cyclin-dependent kinase 5 which are responsible for tau dimerization through phosphorylating it at different sites, which subsequently aggregate into PHF-like filament, resulting in microtubule collapse and neurite retraction²² [Figure 2].

The S1R interaction with ion channels boosts the surface expression of several channels by interacting with them to modulate the ion currents, including voltage-gated potassium ion channel (Kv1.2), voltage-gated sodium ion channels (Nav1.2, 1.4 and Nav 1.5) as well as regulating hERG channels.²² However, they have an inhibitory effect on L-type voltage gated calcium channels, N-type Ca²⁺ channel currents, and some voltage-gated potassium channels (including Kv1.3, Kv1.4, and Kv1.5).²² S1R is strongly abundant at ER membranes that are physically connected to postsynaptic plasma membranes in some types of neurons, such as those in the spinal cord, despite the fact that it has been conclusively shown that S1R is enriched at the MAM.¹⁷ On specialized ER membranes of spinal cord neurons, S1R has been found to colocalize with Kv2.1 potassium channels.³² These results offer the fascinating idea that S1R controls Kv2.1 channel trafficking between the ER and plasma membrane in order to control potassium channel function. Additionally, it has been demonstrated that the Kv2.1 potassium channel contributes to the ER’s attachment to the plasma membrane.^33,34 In addition to impairing the binding of stromal interaction molecule 1 (STIM1) with calcium channel protein 1, they prevent store-operated Ca²⁺ entry.³⁵ Moreover, S1R binds with many GPCRs, including opioid receptors, orexin receptors, growth hormone secretagogue receptors, muscarinic (M2) receptors, cannabinoid receptor 1, and dopaminergic (such as D1 and D2) receptors.^36,37

To illustrate the important functions of S1R, it is reported that S1R agonists’ shared capacity to increase brain derived neurotrophic factor (BDNF) production and TrkB receptor signaling both in vitro and in vivo may help to promote synaptic plasticity and neuronal resilience.³⁸ For instance, the strong S1R receptor agonist pridopidine stimulates neurotrophic signaling by activating the extracellular signal-regulated kinase (ERK), BDNF, and a serine/threonine protein kinase (AKT) pathway.³⁹ TrkB appears to be activated by S1R agonists via both BDNF-dependent and independent pathways, this may entail direct interactions between S1R and the TrkB receptor as well as modulation of BDNF expression and processing.⁴⁰ The platelet-derived growth factor receptor (PDGFR) and the epidermal growth factor receptor (EGFR) are two other receptor tyrosine kinases that are stimulated by S1R.⁴¹

The effect of S1R on neurotransmitters can be demonstrated as follows, the hippocampal CA3 region neurons are activated by glutamate binding with the N-methyl d-aspartate (NMDA) receptor, and the release of monoamines was potentiated by low dosages of S1R agonists.² The activity of the Ca²⁺-activated K⁺ current channel to increase Ca²⁺ influx through the NMDA receptors is prevented by S1R.⁴² Interestingly, the expression of the proteins essential for synaptic plasticity linked to NMDA receptor signaling, including GluN2A and GluN2B subunits in addition to postsynaptic density protein-95, is increased in response to the activity of S1R agonists.⁴³ It is interesting to note that while the S1R agonist reduced glutamate release, it had a biphasic response in gamma amino butyric acid (GABA), which is demonstrated in a way that low doses of NE-100 (a S1R antagonist) boosted GABA absorption, and as the dose grew, the uptake rate dropped.⁴⁴

Through 1, 4, 5-trisphosphate inositol (IP3) receptors at the MAM on the side of the ER, the S1R influences Ca²⁺ release from the ER into the mitochondrion.⁷ As a result, when IP3 stimulates IP3 receptors, significant amounts of Ca²⁺ are produced as Ca²⁺ “puffs” at the MAM, which can then be absorbed into the mitochondrion.⁴⁵ However, there were certain problems regarding the naturally controlling of IP3 to Ca²⁺ regulation and transfer from ER to mitochondria, representing the fact that upon the interaction of their ligand IP3, IP3 receptors quickly degrade.⁴⁶ Also, the amount of Ca²⁺ in the ER lumen appears to affect the stability of IP3 receptors.⁴⁷ It came to evidence the role of S1R with IP3 when Novakova et al.⁴⁸ discovered that S1R ligands increased IP3 in cardiac myocytes and that the rise could be inhibited by the S1R antagonist. It was recognized that S1R might be related to IP3 receptors. The IP3 receptor is one of the main Ca²⁺ release channels at the ER; hence, through controlling IP3 receptors, the S1R might inadvertently promote ER-Ca²⁺ efflux, and one suggestion providing the mechanism of interaction between IP3 and S1R is through a direct protein–protein interaction.⁴⁹ Furthermore, S1R stimulation elevates the level of extracellular acetylcholine through their regulation of both IP3 receptor-gated pools as well as voltage-gated (K⁺ and Ca²⁺) channels, which modulate Ca²⁺ mobilization.⁵⁰

S1Rs’ Role in Oxidative Stress

The activation of S1R restores the mitochondrial physiological balance between pro/antioxidant molecular mechanisms in neurological disease, which abrogates the reactive oxygen species (ROS) generation as shown in Figure 3.^8,34 ER stress sensor proteins control the production of molecular chaperones and keep track of the quantity of misfolded proteins in the ER lumen, other ER stress sensor proteins, such as protein kinase RNA-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF-6), are not concentrated at MAMs, while the stress sensor protein inositol requiring enzyme 1 (IRE-1) is.⁵¹ At the MAM, S1R keeps IRE-1 stable only when IRE-1 is activated (i.e., phosphorylated) under ER stress. S1R connects with IRE-1, prolonging IRE-1’s innate endonuclease activity in CHO cells.⁵² The transcription factor X-box binding protein 1 (XBP1) is expressed when IRE-1 is activated, and this causes the overexpression of various ER chaperones.⁵¹ IT was found that S1R knockdown in neonatal cardiomyocytes reduces nuclear localization of (XBP1) and activated IRE-1, while increasing the expression of many ER stress-related proteins, including C/EBP Homologous Protein (CHOP).⁵³ Also, it has been demonstrated that S1R controls the production of ROS in the mitochondria as well. The interaction of S1R with IRE-1 stabilizing it is brought on by the buildup of mitochondrial ROS. In contrast to S1R overexpression, S1R knockdown causes NF-κB activation and ROS buildup in CHO cells.⁵² Additionally, it has been shown that S1R knockdown hinders the proliferation of cancer cells by causing ER stress and the production of ROS.^8,54,55

Figure 3.

Role of S1R in maintaining cellular hemostasis. When calcium is released from the ER into the mitochondria via IP3Rs, microdomains near the focal MAM are enriched in S1R, which controls calcium signaling between ER and mitochondria. Additionally, S1R functions as an ER lipid scaffolding protein that can interact with and modify cholesterol-rich microdomains, in addition to controlling oxidative stress responses. S1R initiates a positive transcriptional loop that boosts S1R expression via the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eIF2-α/ATF4 pathway in response to ER stress, which strengthens mitochondrial bioenergetics by increasing the calcium leak from the ER into the mitochondria. IRE1α, IP3R, and PERK, eukaryotic initiation factor 2 alpha (p-eIF2α), inhibit caspases, as well as raising B-cell lymphoma 2 (Bcl-2) to aid in the promotion of cell survival.

It was found that S1R, which normally localize at the ER, can translocate to the nuclear envelope where they interact with emerin, emerin then attracts the proteins barrier-to-autointegration factor (BAF) [(histone deacetylase and specific protein 3 (HDAC3)] and forms a complex, which can then suppress the gene transcription of monoamine oxidase B, a gene of critical role in oxidative stress.⁵⁶ Several studies showed that animals lacking the S1R expressed high levels of oxidative stress.^54,57 Likewise, retinal Müller cells missing S1R exhibited elevated levels of ROS.⁸ However, the activation effect of S1R on retinal Müller cells lowered the production of ROS by promoting the nuclear factor (erythroid-derived 2) - like 2 (Nrf2) signaling pathway.^58,59 Moreover, S1R activation decomposes the complex between neuronal nitric oxide synthase (nNOS) with PSD-95, which decreases the total quantity of nitric oxide formed.⁶⁰

Sigma 1 Receptors’ Role in Neuroinflammation

Numerous studies demonstrate that S1Rs improved neuronal survival and restored neuronal functions in neurodegenerative diseases through a variety of mechanisms, such as regulating reactive gliosis, attenuating the production of reactive species, modulating ER and mitochondrial functions, modifying calcium homeostasis and glutamate activities, and promoting neuronal plasticity^61,62 [Figure 3]. S1Rs regulate the activation of microglial cells and reduce neuroinflammation.^62,63 Microglia, cells derived from macrophages that exist in the CNS, are the main mediators of neuroinflammation there.⁶⁴ Despite the fact that CNS injury is thought to cause a variety of microglial phenotypes, they are often categorized as M1 and/or M2 responses, much like peripheral macrophages, M2 microglia are anti-inflammatory and linked to neuronal repair and renewal, whereas M1 microglia are pro-inflammatory and typically associated with CNS injury.^64,65 S1R may influence microglial activation and reduce neuroinflammation since they are expressed in microglia and neurons. S1R agonists may impact M1 and/or M2 responses, as several studies have demonstrated, with the majority of these studies to far focusing on the M1 response^25,38,66 [Figure 4].

Figure 4.

A schematic model showing the effect of S1R on different types of microglia and astrocytes.

Numerous brain cells, including neurons, astrocytes, microglia, and oligodendrocytes, express S1R.⁶⁴ The M1 microglial phenotype and the astrocytic response to inflammatory stimuli are inhibited by S1R activation, whereas the M2 microglial repair and regenerative phenotype is promoted. Additionally, triggering S1R helps mice rehabilitate from an ischemic stroke since it tolerates the overexpression of matrix metalloproteinase 9 and excessive astrogliosis.⁶⁷ Moreover, Zhao et al.⁶⁸ showed that S1R agonist (pentazocine) prevented the activation of c-Jun N-terminal kinase pathways induced by lipopolysaccharide (LPS). Also, it diminished the generation of tumor necrosis factor-α (TNF-α), interleukin 10 (IL-10), and monocyte chemoattractant protein-1. Furthermore, Wu et al.⁶⁹ showed that the allosteric modulator of the S1R “SKF83959” reduced LPS-induced microglial activation in murine microglial BV2 cells and lowered the release of IL-1, and inducible nitric oxide synthase (iNOS). Α further clue: the synthetic S1R SA4503 upregulated the glutathione and unregulated iNOS and TNF-α expression in the inflammation model.^7,70

Role of S1R in Modulating ER Stress

The ER stress is related to many neurodegenerative diseases. Proteins that are unfolded or misfolded accumulate in the ER lumen as a result of ER malfunction. As a result, ER elicits the unfolded protein response (UPR), which is a protective or adaptive response aiming to restore ER equilibrium [Figure 5A]; nevertheless, if the stress signal is strong and/or persistent, ER activates cell death pathways⁷¹ [Figure 5B].

Figure 5.

A schematic diagram showing the three different arms of unfolded protein response (UPR). UPR is activated when there is an accumulation of unfolded proteins in the ER, which helps in cell survival by reestablishing protein folding homeostasis (A). Long-term ER stress counteracts the UPR’s adaptive response and results in apoptosis (B). S1R have been shown to regulate the activity and/or levels of the three main ER stress proteins (ATF6, IRE1α and p-PERK), decrease CHOP, Bcl-2-associated X protein (BAX), Bcl-2 homologous antagonist/killer (BAK), and caspases, as well as raising Bcl-2 to aid in the promotion of cell survival.

The UPR is mediated by three primary signaling pathways: protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6).^72,73 The UPR is modulated by S1Rs, which play a key role as chaperones in the decomposition of unfolded proteins, according to multiple studies.^73,74 The glucose-regulated protein 78 (GRP78)/BiP, a crucial regulator of all three arms of the UPR, has also been shown to interact with the C-terminus on the S1R.⁷³

All three pathways’ downstream activities have been linked to both the induction of apoptosis and adaptive or protective reactions to protein buildup.⁷⁵ PERK reduces global protein translation to lower the protein load on the ER, and IRE1α and ATF6 upregulate UPR-related proteins to enhance ER folding capacity and ERAD. These are examples of adaptive responses. On the other hand, apoptosis may also result from PERK activation. ATF4 is one of the proteins that can evade the translational repression mediated by PERK. The expression of certain apoptotic activators, including as C/EBP-homologous protein (CHOP), is subsequently stimulated by ATF4.⁷⁵

Thus, prolonged PERK activation results in CHOP overexpression, which in turn suppresses antiapoptotic B-cell lymphoma 2 (Bcl-2) expression while increasing that of pro-apoptotic BH3-only proteins. Apoptosis that is dependent on Bak and Bax may be triggered as a result of this series of events.⁷⁶ In order to contribute to caspase-activated apoptotic cell death, IRE1α can also degrade microRNAs that block caspase production and activate c-JUN amino-terminal kinase and apoptosis signal-regulating kinase. ATF6 can also enhance cytochrome C release and decrease Bcl-2 levels, which further activates the apoptotic cascade.⁷⁵

The quantity of misfolded proteins and the timing of the stress exposure determine whether ER stress triggers a pro-apoptotic or UPR-adaptive response.⁷⁶ The UPR is triggered in response to acute stress and moderate misfolded protein buildup in order to restore cellular homeostasis by clearing accumulations via autophagy or the ERAD machinery connected to the ubiquitin proteasome system.⁷⁶ It is fair to think that persistent or severe protein accumulation could induce the ER to trigger cell death rather than cell maintenance programs, even though the threshold for apoptosis is uncertain.⁷⁵ Accordingly, neurodegenerative illnesses like epilepsy, Huntington’s disease, Parkinson’s disease (PD), and Alzheimer’s disease (AD) have been connected to constitutive activity of the ER stress response. While blocking the parts of UPR signaling that encourage apoptosis, therapeutic approaches that are anticipated to prevent neurodegeneration may increase UPR signaling responses that reduce ER stressors.

S1R expression is increased in response to PERK pathway activation after the infusion of the Ca²⁺ channel inhibitor thapsigargin, which is often employed to simulate ER stress and generate UPR in cell culture models and more specifically, ATF4, a downstream target of PERK signaling.^65,77 In line with this, S1R overexpression diminished the activation of PERK and ATF6 and increased cell survival in Chinese hamster ovary cells, whereas S1R knockdown disrupted the conformation of IRE1 and reduced cell survival after thapsigargin administration.^11,17

1. Role of S1R in Epilepsy

Convulsive seizures, which are associated with a heightened risk of sudden unexpected death in epilepsy, are the most common type of recurring, pharmaco-resistant seizures that identify epileptic seizures.^78,79

The S1R has long been linked to disorders that cause seizures, but one of the more recent and intriguing hypotheses about the function of the receptor suggests that it may also mediate nonseizure comorbidities of epilepsy such as cognition decline.^11,80 In Dravet syndrome, a subtype of developmental and epileptic encephalopathies (DEEs), S1R activity was crucial in mediating both the fenfluramine significant clinical advances in executive function and recoveries of cognitive problems.^81,82 The chemoconvulsant GABA_A antagonists, pentylenetetrazol (PTZ) and bicuculline (BIC) increase the likelihood of convulsive seizures in mice with a genetic deletion of S1R (S1R–/−).⁸³ Moreover, neuronal glutamatergic as excitatory and inhibitory (GABAergic) inputs are unbalanced in epileptic seizures. Insufficient GABA_A receptor regulation of glutamatergic signaling, especially that of NMDA receptors, leads to excitatory stimulation and increased seizure abnormalities in epilepsy.⁸⁴ S1R is a potential therapeutic target for managing seizures and nonseizure symptoms associated with both seizure activity and other DEEs because several psychiatric medications bind to S1R.⁸⁵

All the previous findings are rectified by the S1R, implying that it may be a potent pharmaceutical target with the potential to treat neurodegeneration, motor deficiencies, as well as cognitive and behavioral diseases.⁸⁶ Thus, the activity S1R restores the balance between GABAergic and glutamatergic pathways, by which they may carry the potential as a disease-modifying pharmaceutical target.^82,87

In Table 1, a number of experimental and clinical studies have been made and analyzed to obtain the attracted findings which demonstrate the various effects of S1Rs in epileptogenesis and how it can be considered as a therapeutic target for management.

Table 1. Table Demonstrating Some of the Experimental and Clinical Trials Defining the Role of S1R in Epilepsy.

2. Role of S1R in Alzheimer’s Disease

Alzheimer’s disease (AD), the most prevalent type of dementia, is defined by a progressive decline in cognitive function as a result of the hippocampal destruction and impairment of other parts of the brain, which may be caused by autosomal dominant hereditary mutations in presenilin 1 (PS1), presenilin 2 (PS2), or amyloid precursor protein (APP).^94,95 Amyloid beta (Aβ) protein is produced after breaking down of APP by the β- and γ-secretases, and it consists of 39 to 42 amino acid residues.⁹⁶ Presenilins are essential catalytic components of the γ-secretase complex. The extracellular portion of Aβ with a length of 42 amino acid residues (Aβ 42) is promoted by mutations in APP, PS1, and PS2 genes in AD, and its accumulation aids in the development of amyloid oligomers.⁹⁴

According to recent research, PS1 and PS2, which are linked to AD, interact functionally with S1R.⁹⁷ In the ER, PS1 and PS2 create a calcium leak channel. Numerous familial AD-causing mutations in PS1 or PS2 interfere with tonic Ca²⁺ release from the ER through PS1 and PS2 leak channels, causing the ER calcium concentration to rise by lowering its levels in the hippocampal neurons.^98,99

To fully understand how S1R activity can normalize the homeostasis of ER calcium and the incidence of mushroom spines while attenuating other different characteristics of AD disorder, more research is required.^58,100 Moreover, much research has shown that Aβ protein is produced intracellularly at the MAM and may have an impact on how the ER, mitochondria, and MAM operate. Depending on the findings of many studies, the importance of the presence of S1R at MAM has been proven.^17,63,101 In fact, some genotypes of apolipoprotein E and S1R interact genetically to enhance the AD risk.^95,102 Several agonists of S1R have antiamnestic characteristics that help them recover from scopolamine or Aβ toxicity-related learning and memory deficits. Due to S1R’s ability to maintain mature mushroom spines, which act as important sites of strong synaptic activity, their agonists can stimulate neurogenesis in the hippocampus and may ameliorate memory impairment.^11,103

Since the hippocampal neuronal mushroom spines are lost in PS1-M146 V knock-in and APP knock-in models of AD, mushroom spine loss may be the cause of memory deficits in these models of AD.¹⁰⁴ Downregulation of S1R may have a role in AD pathogenesis as brain imaging studies have shown a lower density of S1R in AD patients.⁹⁷ In line with this, S1R deletion in Swedish mutation (APP_swe) AD mice worsens memory deficits by causing oxidative stress in the hippocampus.^104,105 OZP002 protected against the neurotoxicity brought on by the injection of Aβ25–35, decreased learning deficits brought on by scopolamine, the APP_swe transgene, or the injection of amyloid Aβ25–35. The fact that SOMCL-668 increased SKF-10047 -stimulated neurite development and the synthesis of BDNF depending on the interaction with S1R suggests potential application.^92,106

However, recent research suggested that S1R levels can be increased in early AD patients depending on the fact that the S1R is a pluripotent modulator of multiple systems found at the MAM and expressed widely as an index of adaptive responses to cell stress. However, our observation that S1R binding was not increased in patients with AD in the hippocampus, the brain region that showed the biggest differences in mitochondrial and synaptic density compared to controls, suggests that expression of S1R also must be influenced by regionally specific factors.¹⁰⁷ In Table 2, we tried to analyze and figure out the recent and valuable experimental models demonstrating the possible neuroprotective role of S1Rs in the deterioration of AD and demonstrating specific pathways through which we may consider S1R as a therapeutic target in the management of AD.

Table 2. Table Demonstrating Some of the Experimental Defining the Role of S1R in Cognition Impairment Using Several Behavioral Tests Including Morris Water Maze.

Experimental trials
Model	S1R modulator	Reference
Scopolamine	SKF-10047	(108)
Nucleus basalis lesion	Fluoxetine	(109)
Scopolamine	OPC-14523	(110)
Scopolamine	Pentazocine	(111)
Scopolamine	KT-95	(112)
Scopolamine	ANAVEX2-73	(113)
Dizocilpine	DHEA-S	(114)
l-NAME, 7-nitroindazole	pentazocine	(115)
192IgG-saporin-induced lesions, atropine sulfate	PPCC	(116)
Scopolamine	Dimemorfan	(117)
Scopolamine	ANAVEX1-41	(118)
Phencyclidine, dizocilpine	SA4503, pentazocine,	(119)
Dizocilpine	Donepezil, igmesine	(120)
Phencyclidine	Fluvoxamine,	(121)
Phencyclidine	Donepezil	(122)
Nimodipine	PRE-084	(123)
CDEP	SKF-10047, DTG, 3-PPP	(124)
Repeated CO exposure	SKF 10047, DTG	(125)
Repeated CO exposure	Donepezil, igmesine	(126)
Trimethyltin	Igmesine	(127)
Trimethyltin	Dextromethorphan	(128)
Rapid movement of eye	Cutamesine	(129)
Brain ischemia	DHEA	(130)
β-Amyloid(25–35)peptide	Donepezil, PRE084	(126)
J20 amyloidogenic mouse model of AD	Fluvoxamine	(131)
p-Chloroamphetamine	SKF-10047, DTG, and 3-PPP	(132)
APP/PS1	Choline	(133)
Cholinergic lesion and amyloid infusion	MR22	(134)
McGill-R-Thy1-APP transgenic (Tg)	AF710B	(135)
α-thalassemia X-linked intellectual disability	SA4503	(136)
Alcohol withdrawal	BD1047 (antagonist)	(126)
Scopolamine, Injection ofAβ25–35peptide	OZP002 (modulator)	(137)

3. Role of S1R in Parkinson’s Disease

Parkinson’s disease (PD) is a slowly progressing CNS degenerative disorder caused by dopaminergic neuronal loss in both (the substantia nigra and striatum) and the existence of Lewy bodies.¹³⁸ Importantly, PD patients can have dramatically lower levels of S1R receptors in both (the substantia nigra as well as the striatum).¹³⁸ In addition, motor abnormalities and dopaminergic neuron loss are seen in S1R-knockout mice; these abnormalities may be spurred on by the phosphorylation of α-synuclein, which in response to oxidative stress it forms an aberrant structure.¹³⁹

S1Rs may reduce dopamine-induced toxicity in PD in addition to reducing neuro-inflammation.¹⁴⁰ Both enzymatic and auto-oxidation of endogenous dopamine can result in ROS production and degenerative damage to dopaminergic neurons. According to Mori and colleagues, CHO cells exposed to dopamine enhanced the basal levels of ROS in S1R knockdown cells and increased intracellular ROS in wildtype cells.¹⁴⁰ Furthermore, Bcl-2 overexpression prevented the apoptosis observed by the dopamine/S1R knockdown combination. In S1R knockdown cells, dopamine also enhanced NF-κB activation and Bcl-2 protein downregulation. These findings imply that the S1R-NF-κB-Bcl-2 pathway is essential in preventing dopamine-induced apoptosis.¹⁴⁰

Experimental PD models have demonstrated the effectiveness of S1R agonists. Francardo et al.¹⁴¹ revealed that mice with a unilateral striatal hydroxydopamine lesion considerably enhanced their motor skills after undergoing a continuous infusion of the S1R agonist PRE-084.¹⁴² A study on PD-affected macaques indicated that pridopidine can lessen the dyskinesia brought on by 3, 4-dihydroxyphenylalanine. This study demonstrated that S1R may potentiate the effect of anti-Parkinsonians, which was clued by the presence of interactions with other receptors, including α2C, dopamine D3, and serotonergic 5HT1_A receptors, when an effective dose was given.¹⁴² Additionally, PRE084 activated the trophic factor mediators ERK 1 and 2 (ERK1/2) and AKT, and it elevated several neurotrophic factors, including BDNF.¹⁴³ According to these results, functional recovery in PD may be facilitated by the restoration of synaptic connections. Notably, PRE084 therapy significantly reduced M1 microglial responses brought on by 6-hydroxydopamnie lesions, and neuro-inflammation plays a major role in the etiology of PD.¹⁴³

Amantadine, a medication prescribed for the treatment of PD, modulates glutamatergic and cholinergic transmission. Additionally, it increases the activation of G-protein as a result of dopamine-induced calcium transport and is mitigated by “BD1047” a S1R antagonist.¹⁴²

Preclinical studies have dominated the study on S1R agonists in PD up to this point. The effectiveness of the S1R agonist “ANAVEX2–73” in treating patients with PD and contemporaneous cognitive impairment is being studied in the second phase of a clinical study.¹⁴⁴ In the same line, a phase 2 clinical trial defining the effect of pridopidine on L-DOPA-induced dyskinesia in patients with PD.¹⁴⁵ However, the effectiveness of this medication is yet uncertain because the findings of this trial have not yet been finished.

In conclusion, a variety of pathophysiological variables, such as excitotoxicity, ROS, neuroinflammation, and pathogenic alpha-synuclein aggregation, contribute to neurodegeneration. Through a variety of methods, agonist-induced S1R activation offers neuroprotection. Increased pathogenic alpha-synuclein aggregation has been shown in S1R KO mice, whereas alpha-synuclein breakdown has been observed in S1R agonists. This demonstrates how S1R contributes to alpha-synuclein aggregation. Furthermore, S1R activation reduces the inflammatory response and microglial activation. By blocking NMDA receptors, S1R agonists prevent glutamate-mediated excitotoxicity. Moreover, endogenous antioxidant gene expression is modulated by S1R agonists. S1R is a perfect therapeutic target for PD because of all these characteristics.

4. Role of S1R in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), a deadly neurodegenerative condition causing progressive motor neuron loss in the brain, which results in gradual muscle atrophy. Disorders associated with ALS are brought on by an intracellular buildup of mutant and improperly folded proteins.¹⁴⁶

Juvenile ALS has been demonstrated to be caused by an E102Q autosomal-recessive mutation in the S1R, albeit only in one family.¹⁴⁷ More recently, it has been shown that overexpression of the E102Q S1R in Neuro2A cells causes the mutant S1R to aggregate, which in turn reduces mitochondrial ATP generation and causes the TAR DNA binding protein, TDP43, to mislocalize from the nucleus to the cytoplasm. Methyl pyruvate could be added to prevent this effect of the E102Q mutation and preserve mitochondrial ATP synthesis.¹⁴⁸

According to an autosomal recessive phenotype, which requires a mutation on two alleles, ALS in humans can be caused by the S1R’s malfunction.¹⁴⁹ Additionally, ALS was caused by a mutation in the human S1R gene’s 3′ untranslated region. In this instance, having a single allele mutation was enough to for the illness to manifest. Conversely, S1R knockout mice do not acquire ALS. However, the protective effect of S1R in ALS has been demonstrated in ALS model mice, where behavioral and lifespan investigations have shown that the presence of a mutant superoxide dismutase 1 (SOD1 G*93A mouse model) and a lack of S1R (S1R KO) exacerbated the disease progression.¹⁴⁹

Locomotor deficits and loss of motor neurons have been shown in S1R-knockout mice.¹⁵⁰ PRE-084 (a S1R agonist) enhanced the motor behavior of the tested animals and their survival rate when administered chronically against SOD1 mutant mice.¹⁵¹ Moreover, “SA4503″, acting as an S1R agonist, demonstrated elevated survival in the diseased animals with ALS but not improved locomotor function.¹⁵² In addition, administering the agonist of S1R “pridopidine” reduced mutant SOD1 accumulation and enhanced motor neuronal function. Signaling pathways such as (protein kinase C, a serine/threonine protein kinase, and ERK) have regularly been linked to the positive benefits of S1R agonists in all of the previous studies.^22,39

5. Role of S1R in Huntington’s Disease

Huntington’s disease (HD) is a CNS disease resulted from mutations in the IT15 gene, which encodes the huntingtin protein and increases the frequency of CAG nucleotide repeats.¹⁵³ The development of aberrant huntingtin that accumulates inside the different neurons and damages them before eventually eradicating them thus is correlated with the presence of 36 CAG repeats, as a healthy person has 35 or fewer CAG repeats. There are several molecular mechanisms contributing to neuronal death-mediated movement abnormalities and gradual cognitive impairment in HD, which may be aberrant calcium regulation due to glial reactivity, oxidative stress, and decreased axonal transport.^7,22

Hyrskyluoto et al.¹⁵⁴ showed that the neuroprotection activity of S1R agonist PRE-084 in counteracting the harmful effects and improved neuronal survival in cell lines PC6.3, which have 120 glutamine repeats (120 Q-huntingtin) carrying mutant huntingtin proteins but have a lesser number of S1R receptors. The S1R agonist ZNF-179 overexpressed the antioxidant components and decreased the ROS.¹⁵⁵ Furthermore, Miki et al.¹⁵⁶ found that patients with polyglutamine disease such as HD treated by thapsigargin can cause S1R to migrate in the nucleus. Interestingly, S1R may be linked to the removal of various aberrant proteins responsible for the presence of HD disease from cell nuclei.

Using S1R-selective fluspidine PET, it was demonstrated for the first time in vivo a high and selective S1R receptor occupancy (approximately 90%) by pridopidine in patients with HD, at a dose of 90 mg (plasma exposure correlates to 45 mg bid at steady state).¹⁵⁷ S1R occupancy as a function of pridopidine dose or plasma concentration in healthy volunteers can be described by a three-parameter Hill equation with a Hill coefficient larger than 1 for pridopidine doses ranging from 0.5 to 90 mg and respective plasma concentrations. S1R occupancy drops below 50% at a pridopidine dose around 1% of the highest original dose of 90 mg. There are no significant differences in S1Rs occupancies between healthy volunteers and patients with HD at 90 mg pridopidine. In contrast, using fallypride PET, it was showed that the D2/D3R occupancy of pridopidine 90 mg is negligible (∼3% RO).¹⁵⁷

Pridopidine shows a S1R-dependent neuroprotective effect against mutant Huntingtin induced cell death in vitro and in vivo in cortical and striatal neurons in experimental HD mice.¹⁵⁸ Pridopidine decreases motor and behavioral symptoms and rescues transcriptional abnormalities in the striatum via the S1R in a YAC128 mice experimental HD model. Pridopidine enhances BDNF levels in mice brains of experimental HD.¹⁵⁸

In addition to interfering with ERAD, HD increases IP3R sensitivity to IP3, which causes a tonic calcium leakage that lowers ER Ca²⁺ levels, another factor contributing to ER stress.¹⁵⁹ By altering IP3R transport of Ca²⁺, pridopidine activation of the S1R may hasten HD sequestration into massive aggregates that are significantly less toxic, hence lowering ER stress.¹⁶⁰ By activating the S1R, pridopidine inhibits aberrant ER Ca²⁺ release in YAC128 HD primary neuronal cells.¹⁶¹

7. Role of S1R in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune and inflammatory demyelinating disease of the CNS in which the myelin sheath is damaged in most central and peripheral neurons resulting in, sensory, visual, urological, autonomic, mental, cognitive, and cerebellar impairments. Young adults are more likely to be diagnosed with MS, and it frequently causes serious neurological issues.¹⁶² Numerous studies showed that S1R ligands have been associated with the formation of myelin and oligodendroglial proliferation.^97,163

Dextromethorphan, a S1R agonist, prevented experimentally generated encephalitis in different models of multiple sclerosis.¹⁶⁴ S1R agonists AVANEX 2–73 and Dextromethorphan, also reported that they decreased apoptosis and excitotoxicity in oligodendroglia and oligodendroglial precursors.¹⁶⁵

8. Role of S1R in Visual Disorders

Elevated affinity for the purpose of researching S1R functions in the retina, S1R-selective agonists, such as (+)-pentazocine, PRE084, and SK10047, and antagonists, such as NE100, BD1047, and BD1063, offer practical medications.⁷⁴ Early research indicated a neuro-protective function of S1R in the retina by treating animals (or cells) with S1R ligands and analyzing entire retina samples.¹⁶⁶ In recent research, researchers examined cell type-specific S1R activities in the retina, taking use of the layered retinal structure that divides various neurons.^167,168 a majority of S1R functional studies in the retina have focused on ganglion neurons and associated disease conditions. Studies have also been extended to other cell types, e.g., Müller glia and microglia.^167,168

Numerous study groups’ in vitro and in vivo investigations provide evidence for S1R’s pro-survival function in retinal ganglion cells.¹⁶⁷ The Smith group demonstrated that the S1R-specific agonist (+)-pentazocine prevented apoptosis brought on by homocysteine or glutamate using both primary mouse retinal ganglion cells and retinal ganglion-5 cell line.^168,169 The NMDA receptor mediated the mitigation of excitotoxicity, which was identified as the mechanism. Additionally, (+)-pentazocine shielded retinal ganglion-5 cells against oxidative stress, according to a recent study; this effect was linked to the down-regulation of ER stress proteins.^167,168

The Smith group found a strong antioxidative effect of S1R activation in an in vivo investigation employing a spontaneous diabetic retinopathy mice model. Injecting (+)-pentazocine into the mice maintained the Müller glia’s organization and thickness.¹⁶⁹

One type of hereditary retinal progressive degenerative disease is retinal pigmentosa (RP) which characterized by abnormalities of the retinal pigment epithelium and impairment of photoreceptors, which ultimately lead to loss of vision. To preserve the integrity of the retinal architecture, RP therapy now employs neuroprotection as a tactic.¹⁷⁰ S1Rs are expressed in both photoreceptor cells and cell lines, as was previously indicated, and they are essential for preventing damage to photoreceptor cells. Studies on in vitro pharmacology revealed that 661W expressed S1Rs. When 661W cells were exposed to light, SA4503 decreased the amount of oxidative stress and the expression of genes related to antioxidants. It also increased the expression of the S1R and decreased the damage caused by light exposure.¹⁷¹

According to an in vivo investigation, intraperitoneal treatment of (+)-PTZ for a few weeks at p14 improved cone function. Additionally, immunofluorescence staining showed a decrease in cone nucleus loss and an increase in photopic responses at p35. Additionally, following (+)-PTZ injection, the detachment of photoreceptor cells and the thickness of the whole retina were maintained at p42 and p21. The (+)-PTZ-rd10 group showed less loss of photoreceptor cell nucleus at p42, according to the histomorphology analysis results. In the meantime, (+) PTZ therapy functioned as a “protective molecule” in other processes, such as the degree of oxidative stress experienced by proteins and lipids. The aforementioned protective effects on cone cells were reversed in S1R-deficient rd10 animals, indicating the critical involvement of S1R in RP.¹⁷² Subsequent research revealed that rd10 mice’s early S1Rs intervention with (+)-PTZ at p14 offered a deeper level of photoreceptor protection than treatment at p18, p21, and p24. The (+)-PTZ-rd10 group outperformed the others in terms of retinal structure, electroretinogram amplitude, and visual acuity as measured by optokinetic tracking system recoding.¹⁷³ The sole agonist that demonstrated in vivo protection in rd10 mice was (+)-PTZ, in contrast to SA4503 and PRE-084.¹⁷⁴ However, the aforementioned outcomes were decreased in S1R knockout rd10 mice. The investigation that followed revealed that the antioxidant signaling pathway Nrf2 had a role in the S1R to photoreceptor cells’ neuroprotection.¹⁷⁵ The loss of whole retinal cells was made worse by S1R deletion. Rod photoreceptor cells were lost in S1R knockout rd10 mice prior to 5 weeks of age, whereas cone loss worsened after 6 weeks. Likewise, Müller cells that expressed more glial fibrillary acidic protein, oxidative stress, and ER stress-associated signal molecules experienced an acceleration of gliosis. In S1R knockout rd10 animals, for instance, the expression of the autophagy marker LC3-II, the apoptotic protease caspase3, and the ER stress markers was significantly elevated early on.^176,177

9. Role of S1R in Wolfram Syndrome

Uncommon hereditary condition that affects numerous body parts is Wolfram syndrome (WS), sometimes referred to as diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD). It results from mutations in the WFS1 gene, which codes for the production of the wolframin protein. The disorder’s most prevalent symptoms are deafness, optic atrophy (damage to the optic nerve that can result in vision loss), diabetes mellitus (a condition that affects how the body consumes and stores glucose), and diabetes insipidus (a disorder that causes excessive thirst and urination). Neurological issues like ataxia (difficulty with balance and coordination), seizures, behavioral issues, urinary tract issues, and mental health conditions can also be a part of wolfram syndrome.¹⁷⁸

The wolframin protein is expressed in the ER, interacts with the MAM, and facilitates the movement of calcium from the ER to the mitochondria.¹⁷⁹ Wolframin mutations cause mitochondrial malfunction and cell death by interfering with calcium transport. When it comes to chaperoning proteins like the IP3R and calcium transport between the ER and mitochondria, the S1R plays a significant role. Calcium moves from the ER to the mitochondria when S1R is activated, either by an agonist or during cellular stress. This lowers ER stress, protects the mitochondria, raises cellular ATP levels, and enhances cell health overall.⁵² Overexpression of S1R reduced symptoms and restored calcium homeostasis in vivo and in vitro in wolfram syndrome models in mice and zebrafish.¹⁸⁰

A good model for examining the roles of S1R is the retina, which is made up of a variety of cell types. Understanding the function of S1R in retinal degenerative diseases has advanced significantly over the last ten years. Although retinal ganglion neurons have received the most of attention, there are now reports of S1R in other retinal cell types. Further research is needed to fully utilized the therapeutic potential of an S1R-targeted approach to treating retinal disorders.

10. Role of S1R in Rett Syndrome

An uncommon hereditary neurodevelopmental illness called Rett syndrome affects how the brain develops and can lead to intellectual, cognitive, and physical problems. Females are more likely to have RS.¹⁸¹ It has been shown that the loss-of-function mutation of the methyl CpG binding protein 2 (MECP2) gene, which is found on the X chromosome Xq28, is the most specific cause of Rett syndrome. Numerous other gene expressions at the transcriptional and post-transcriptional levels can vary either positively or negatively when MeCP2, an epigenetic regulator of gene expression that functions as a transcriptional activator and repressor, malfunctions. Neurological dysfunction and subsequent phases of brain development are similarly impacted by MeCP2 absence.¹⁸²

Rett syndrome is a broad category of neurologic abnormalities. There seems to be little to no confirmed causal relationship between the S1R and the development of Rett syndrome, in contrast to certain neurodegenerative disorders.¹⁸¹ However, the S1R is a target for treating the neurological damage found in Rett syndrome because of its promiscuous connection with several proteins and signaling pathways in the brain, as well as its relative success as a target for treating other neurodegenerative disorders. A mutation in the MeCP2 gene is present in the majority of cases. High amounts of MeCP2 are present in neurons and are linked to the CNS’s maturation and synaptic plasticity. Although there is some evidence that MeCP2 activates some genes, it is generally believed to adversely affect gene expression.¹⁸³

S1R is known to have a role in regulating BDNF expression in multiple cellular systems,¹⁸⁴ and numerous studies have found that S1R agonist treatment of various cells results in AKT phosphorylation.¹⁸⁵ Additionally, S1R activity has a role in autophagy regulation, becoming a novel target for treating neurological disease.¹⁸⁶ BDNF is one protein that MeCP2 is thought to negatively regulate, along with the mTOR/AKT signaling pathways.¹⁸⁴

11. Role of S1R in Parkinson’s Disease

Parkinson’s disease (PD) is a prevalent neurological illness that causes motor symptoms and CNS dysfunction. The initial symptoms are typically bradykinesia, or sluggish movement, or tremors in one hand that cause rigidity (rigid muscles).¹⁸⁷ Additional symptoms may include speech and writing difficulties, poor balance, and the loss of automatic motions like smiling, blinking, and arm swinging while walking. Since most of the hallmark symptoms of PD appear later and dopaminergic neurons have already been damaged, a number of biomarkers have been developed to detect the disease early.¹⁸⁷

Similar to AD, PD is characterized by decreased S1R expression, and S1R knockout animals exhibit age-related dopaminergic neuron loss. In PD, the S1R may also lessen dopamine toxicity.¹³⁹ Ischemia, hypoxia, and local exposure to neurotoxins, such as high levels of excitatory amino acids and methamphetamine, can all raise dopamine levels.¹⁸⁸ High dopamine availability can also operate as a neurotoxic. An imbalance in REDOX management is associated with the dopamine neurotoxicity pathway. ROS and dopamine-quinones can be produced by the spontaneous oxidation of dopamine in vitro or by an enzyme-catalyzed process in vivo.¹⁸⁸ When DA-quinones attach to cysteine or cysteinyl residues on proteins, glutathione homeostasis becomes unbalanced.¹⁸⁸ When S1R knockdown CHO cells and wild-type CHO cells are exposed to physiologically appropriate dopamine doses, ROS levels rise.¹⁴⁰ However, only the S1R knockdown cells exhibit an increase in apoptosis.¹⁴⁰ Additionally, this S1R agonist dipentylamine can inhibit ROS-mediated apoptosis in dopamine-treated Neuro2A cells that express APP^SWE (this protective effect itself was reversed by S1R antagonist BD1047).^189,190

It has been determined that mutations in genes linked to Parkinson’s disease (PD), including α-synuclein, DJ-1, LRRK-2 (which encodes leucine-rich repeat kinase 2), and GBA (which encodes glucocerebrosidase), result in aberrant α-synuclein proteostasis, which causes mitochondrial dysfunction, oxidative stress, neuroinflammation, and pathophysiology of the motor circuits.¹⁹¹ Patients with PD have been shown to have oxidative damage to the substantia nigra. Cell death and α-synuclein aggregation are accelerated by oxidative stress.¹⁹² S1R ligands have been found in numerous studies to lower oxidative stress using a variety of in different models through different signaling pathways that involve preserving the mitochondria and ER.^8,59,193

12. Conclusion and Future Perspectives

It has been demonstrated that scientists have planned to investigate the possible role of S1Rs in a few certain physiological functions and illnesses. The S1R research community is probably motivated by the belief that S1R modification may be a therapeutic approach. In line with this, a lot of work has been done in the field of medicinal chemistry to produce specific ligands that may 1 day be turned into medications. Our study indicates that neuroprotection and neurodegenerative disorders are the primary conditions in which the S1Rs have been investigated.

Apart from the well-known lack of success in turning basic research into new medications with obvious therapeutic potential and challenges associated with drug discovery programs, the scientific community, including biopharmaceutical companies, may not have put enough effort or interest into the development of selective S1R ligands that have been approved for use in humans. Additionally, as indicated by the volume of recent publications, there is now just one pharmaceutical business actively publishing in the field—that of generating selective therapeutic ligands for the S1R. Furthermore, the low success rate in turning fundamental research into novel medications with obvious therapeutic potential may also be influenced by the biology of the S1R. The S1Rs is frequently referred to in articles as an “enigmatic protein whose molecular mechanism of action remains elusive”.

According to the most referenced article in our bibliometric study,¹⁷ the S1R is not a conventional receptor because it functions as a molecular chaperone. Chaperones make sure that every protein folds correctly and functions as intended in the appropriate location at the appropriate time. In certain situations, their protein clients bind in distinct conformations, while in other cases, they recognize and bind in conformational ensembles that are locally extremely dynamic and interconvert. Therefore, drug development programs should take into account the inherent challenge of trying to unravel the secrets of this distinct ligand-regulated molecular chaperone in order to turn fundamental research into new medications with a demonstrable therapeutic potential.

In conclusion, a larger level of scientific interest and involvement in this mysterious chaperone, coupled with a corresponding rise in scientific output, should aid in the discovery of new functions and the expansion of those that are already understood in the years to come. New conceptual frameworks and ground-breaking discoveries from recent and upcoming developments in the “chaperone field,” as well as cooperative, synergistic initiatives that combine resources and expertise from various laboratories to overcome the limitations of the individual approaches, are likely to provide the extra boost required to improve research performance. In addition to opening doors for cooperation among research teams with comparable scientific interests in the field of S1R, this study might serve as a useful foundation for selecting significant subjects for further investigation.

Glossary

Abbreviation

AD

Alzheimer′s disease

ALS

Amyotrophic lateral sclerosis

APP

Amyloid precursor protein

ATF4

Activating transcription factor 4

AKT

A serine/threonine protein kinase

BAF

Barrier-to-autointegration factor

BAK

Bcl-2 homologous antagonist/killer

BAX

Bcl-2-associated X protein

BCL-2

B-cell lymphoma 2

BDNF

Brain derived neurotrophic factor

BIC

Bicuculline

BiP

Binding immunoglobulin protein

CHOP

C/EBP Homologous Protein

CNS

Central nervous system

DEE

Developmental and epileptic encephalopathies

DHEA

Dehydroepiandrosterone

DTG

1,3-di-(2-tolyl guanidine)

EGFR

Epidermal growth factor receptor

ERAD

ER associated degradation

ER

Endoplasmic reticulum

ERK

Extracellular signal-regulated kinase

eIF2α

Eukaryotic initiation factor 2 alpha

ERK

Extracellular signal-regulated kinase

GABA

Gamma-aminobutyric acid

GFAP

Glial fibrillary acidic protein

GLT-1

Glutamate transporter 1

GRP78

Glucose-regulated protein 78

GPCR

G-protein coupled receptor

HD

Huntington’s disease

HDAC3

Histone deacetylase and specific protein 3

IL-10

Interleukin 10

iNOS

Inducible nitric oxide synthase

IP3

Inositol triphosphate

IRE1α

Inositol requiring enzyme 1α

JAK2

Janus kinase 2

LPS

Lipopolysaccharide

M1R

Muscarinic acetylcholine receptor

MAM

Mitochondrial associated membrane

MES

Maximal electroshock

MeCP2

methyl CpG binding protein 2

MS

Multiple sclerosis

NMDA

N-methyl d-aspartate

nNOS

Neuronal nitric oxide synthetase

NO

Nitric oxide

Nrf2

Nuclear factor (erythroid-derived 2)-like 2

OZPOO2

3,3,5,5- tetramethyl-2-oxo-oxazaphosphinane

PD

Parkinson’s disease

PERK

Protein kinase RNA-like endoplasmic reticulum kinase

PDGFR

Platelet-derived growth factor receptor

PI3

Phospho-inositide 3-kinase

PS1

Presenilin 1

PS2

Presenilin 2

PTZ

Pentylenetetrazol

RP

Retinal pigmentosa

ROS

Reactive oxygen species

SE

Status epilepticus

SoD1

Superoxide dismutase 1

S1R

Sigma 1 receptor

STIM

Stromal interaction protein

TLR4

Toll-like receptor 4

TNFα

Tumor necrosis factor alpha

TrKB

Tropomyosin receptor kinase B

UPR

The unfolded protein response

VDAC2

Voltage-dependent anion channel 2

VPA

Valproate antiepileptic medication

XBPs

X-box binding proteins

Data Availability Statement

All data used for the review article have been cited in the text.

This review article did not receive any financial support from any organization.

The authors declare no competing financial interest.