The Curious Story of Sigma-1 Receptors

I just finished rereading a review article published in 2009 on the topic of the sigma-1 receptor (S1R), which stated¹:

In conclusion, in some ways the ‘sigma enigma’ has been solved, but what comes with the unraveling of the enigma are more questions.

And boy, were there more questions! The good news is that much has been discovered over the past 17 years. Despite this, it is curious that such an important receptor, which participates in so many diverse and critical intracellular processes, remains an untold story in most of medicine. To be fair, for all that we have learned about S1Rs, we still cannot provide a comprehensive explanation that could serve as an adequate biography.

The Sigma-1 Receptor

The sigma receptor, which is actually 2 very different sigma receptors, was originally thought to be an opioid receptor. Further characterization confirmed that the sigma receptor had a unique amino acid sequence, with no similarity to any other mammalian protein, and was highly conserved across evolution.

Although much is known about S1Rs, very little is known about S2Rs. The successful cloning of the S1R gene SIGMAR1 accelerated the understanding of the highly heterogeneous properties of SR1. Significantly, S1Rs are highly prevalent in neurons, microglia, and astrocytes of the central nervous system, especially in the limbic system and in motor-control neurons.²

S1R is a transmembrane protein; in its resting state, it is located in the endoplasmic reticulum (ER) membrane bound to BiP. Referred to as a chaperone protein, S1R is unlike other chaperone proteins that transiently bind to recently synthesized polypeptides to assist in their correct assembly, stabilization, and transport while preventing misfolding and aggregation, and then dissociate. S1Rs serve as regulatory chaperones that modulate other signaling proteins across wide-ranging intracellular functions.

S1Rs are highly concentrated in the ER region that is in contact with mitochondria, known as the mitochondrial-associated membrane (MAM). Once activated by either a ligand or ER stress (eg, calcium ion imbalance, oxidative stress, or the accumulation of misfolded proteins), S1Rs translocate to many intracellular locations, including the nuclear, mitochondrial, and plasma membranes. Activated S1Rs bind to and modulate ion channels, G-protein coupled receptors, inositol phosphates, and protein kinases, and play a primary role in communication between the ER and mitochondria.

Activated S1Rs demonstrate significant neuroprotective effects and inhibit neurodegeneration through multiple mechanisms, including decreasing ER stress; activating mitochondrial functions, including ATP production; regulating calcium homeostasis; and reducing inflammatory responses. Additionally, S1Rs have neurotrophic properties that can restore previously decreased functions and activate neuronal plasticity.³ Remarkably, S1Rs have been shown to interact with at least 49 unique proteins.

Endoplasmic Reticulum

The ER can be thought of as a large, tube-like organelle within eukaryotic cells, enclosed by a membrane and extending from the nuclear membrane to the outer cell membrane, forming a ubiquitous membrane-bound network throughout the cytoplasm. It is responsible for protein synthesis, folding, processing, and distribution throughout the various compartments of the cell. Additionally, the ER synthesizes lipids and plays a crucial role in intracellular calcium storage and transport. A wide range of physiological and pathological conditions, including calcium dysregulation and oxidative stress, can disrupt ER homeostasis. This results in the accumulation of unfolded or misfolded proteins in the ER, triggering ER stress and activating the unfolded protein response (UPR), which restores homeostasis.

Three signaling pathways manage the UPR: PERK, IRE1alpha, and ATF6. All 3 of these pathways can contribute to either correcting ER stress through protective responses to misfolded protein accumulation or, if the situation is dire, facilitating apoptosis. S1Rs have been shown to increase the activity and/or levels of these 3 ER stress proteins that comprise the UPR.

Maintenance of protein homeostasis is crucial for healthy brain functioning. The abnormal folding and accumulation of proteins is commonly seen in neurodegenerative diseases as well as depression. Additionally, S1Rs act on neurotransmitter systems that are believed to contribute to depression in humans, including acetylcholine, dopamine, glutamate, norepinephrine, and serotonin, as well as regulating the excitatory/inhibitory balance of glutamate/GABA, which is involved in maintaining maximal circuitry function. S1Rs bind to and stabilize ion channels and G-protein coupled receptors, as well as optimizing NMDA-glutamate receptor function.⁴

Mitochondrial Dysfunction

Mitochondria are crucial organelles in all eukaryotic cells, generating ATP, the primary source of cellular energy that drives metabolic processes, as well as regulating calcium homeostasis and facilitating apoptosis. Mitochondrial dysfunction is a contributor to many neurodegenerative diseases. Activation of S1Rs by agonists has been shown to increase calcium transport from the ER into the mitochondria by stabilizing ITPR3 at the MAM, facilitating a return to intracellular calcium homeostasis.

Neuroinflammation

The primary mediators of neuroinflammation are in the brain microglia. Remarkably, microglia can develop into 1 of 2 opposing functional phenotypes: M1, which are proinflammatory, or M2, which are anti-inflammatory. M1 microglia release inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. In opposition, M2 microglia secrete various neurotrophic factors, including BDNF, which promote neuronal repair and regeneration. S1R agonism decreases the release of pro-inflammatory factors from M1 and appears to facilitate microglial transformation from M1 to the M2 anti-inflammatory phenotype.

S1Rs in Neurodegenerative Disorders

Neurodegenerative disorders (eg, depression, Alzheimer disease, Huntington disease, Parkinson disease) often share common processes (eg, calcium dysregulation, damage by oxidative stress, excitotoxicity, mitochondrial dysfunction, and ER stress) that contribute to neuronal dysfunction and disease.⁵ Microglia and astrocytes provide protective functions that attempt to mitigate neurodegeneration.

S1Rs exist in both neurons and glial cells and, through wide-ranging mechanisms, help minimize physiological changes known to increase neurodegeneration. They activate multiple mechanisms to blunt excitotoxicity and calcium ion overload, which would otherwise increase the likelihood of apoptosis and neuronal death. These disorders include neuronal ischemia, which leads to glutamate release that can cause excitotoxic damage, and S1R agonists have been observed to decrease this glutamate release by modulating activity at the NMDA receptor.

Medications With S1R Agonism

Fluvoxamine. Researchers discovered in 1996 that fluvoxamine demonstrated a strong affinity to the S1R.⁶

With this in mind, several independent groups explored the potential positive role of fluvoxamine during the COVID-19 pandemic. Collectively, their work supported the hypothesis that individuals treated with fluvoxamine soon after confirmed SARS-CoV-2 infection could experience a less severe course of illness.⁷ They found that by binding to S1R, fluvoxamine reduced inflammatory cytokine production (inhibiting the cytokine storm) and restored protein folding homeostasis in the ER, thereby curbing hyperinflammation and cellular stress. In essence, fluvoxamine acted as an anti-inflammatory and cellular stabilizer by targeting the S1R pathway, protecting against the damaging inflammation and cellular disruption caused by COVID-19.

Dextromethorphan.⁸ The FDA approved dextromethorphan in 1954 as an antitussive, yet the mechanism of action of this effect eludes us to this day. Over the decades, dextromethorphan has been extensively studied; additional receptor activities identified include agonism of the S1R, uncompetitive antagonism of the NMDA-glutamate receptor, and antagonism of the serotonin transporter. The novel antidepressant dextromethorphan/bupropion combination was FDA approved in 2022 and, although the definitive mechanism of action is not known, it is hypothesized that S1R agonism contributes to its antidepressant effect.

The Story Continues

It has been 50 years since the discovery of S1R, and a remarkable amount of functional activity has been delineated. Despite this, it remains clinically hidden in the shadows of our nomenclature.

S1Rs orchestrate so many divergent mechanisms throughout the neurons, microglia, and astrocytes, so it is easy to become overwhelmed when attempting to understand the full story as we know it.

Now it is your turn to add to the story by learning more and leveraging that information as you consider psychopharmacological options for your patients. Let the curiosity continue!

Dr Miller is Medical Director, Brain Health, Exeter, New Hampshire; Editor in Chief, Psychiatric Times; Volunteer Consulting Psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.

References

1. Maurice T, Su TP. The pharmacology of sigma-1 receptors. Pharmacol Ther. 2009;124(2):195-206.

2. Eskandari K, Bélanger SM, Lachance V, Kourrich S. Repurposing sigma-1 receptor-targeting drugs for therapeutic advances in neurodegenerative disorders. Pharmaceuticals (Basel). 2025;18(5):700.

3. Yang K, Wang C, Sun T. The roles of intracellular chaperone proteins, sigma receptors, in Parkinson’s disease (PD) and major depressive disorder (MDD). Front Pharmacol. 2019;10:528.

4. Ren P, Wang J, Li N, et al. Sigma-1 receptors in depression: mechanism and therapeutic development. Front Pharmacol. 2022;13:925879.

5. Nguyen L, Lucke-Wold BP, Mookerjee SA, et al. Role of sigma-1 receptors in neurodegenerative diseases. J Pharmacol Sci. 2015;127(1):17-29.

6. Narita N, Hashimoto K, Tomitaka S, Minabe Y. Interactions of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brain. Eur J Pharmacol. 1996;307(1):117-119.

7. Hashimoto Y, Suzuki T, Hashimoto K. Old drug fluvoxamine, new hope for COVID-19. Eur Arch Psychiatry Clin Neurosci. 2022;272(1):161-163.

8. Xiao N, Yin L, Teopiz KM, et al. The sigma-1 receptor: a mechanistically-informed therapeutic target for antidepressants. Expert Opin Ther Targets. 2025;29(6):345-359.