Sigma-1 receptor

Structure

The mammalian σ1 receptor is an integral membrane protein composed of 223 amino acids. Despite being found in mammals, it shows no sequence homology to other mammalian proteins. However, it shares 30% sequence identity and 69% similarity with the ERG2 gene product of yeast, a C8–C7 sterol isomerase involved in the ergosterol biosynthesis pathway. Hydropathy analysis reveals three hydrophobic regions within the σ1 receptor. A crystal structure of the human σ1 receptor was first published in 2016.

The sigma-1 receptor is a small, unique integral membrane protein predominantly localized to the endoplasmic reticulum (ER). It is structurally distinct from all other known mammalian proteins. High-resolution crystal structures have shown that the receptor forms a homotrimer, with each protomer consisting of a single N-terminal transmembrane helix, a cupin-like β-barrel domain that contains the ligand-binding site, and a C-terminal V-shaped two-helix bundle that functions as a lid over this pocket. The ligand-binding pocket is highly conserved and predominantly hydrophobic, shielded from the aqueous environment. Key residues such as Glu172 and Asp126 play crucial roles in coordinating ligand interactions. This structural organization enables the receptor to bind a wide variety of ligands and interact with multiple effector proteins. Conformational changes in the β-barrel domain and the helical lid are believed to regulate ligand access and receptor activation. The receptor's architecture supports its function as a chaperone and modulator of numerous intracellular signaling pathways.

Function

A variety of specific physiological functions have been attributed to the σ1 receptor. Chief among these are modulation of Ca2+ release, modulation of cardiac myocyte contractility, and inhibition of voltage gated K+ channels. The reasons for these effects are not well understood, even though σ1 receptors have been linked circumstantially to a wide variety of signal transduction pathways. Links between σ1 receptors and G-proteins have been suggested such as σ1 receptor antagonists showing GTP-sensitive high-affinity binding; there is also, however, some evidence against a G-protein coupled hypothesis. The σ1 receptor has been shown to appear in a complex with voltage gated K+ channels (Kv1.4 and Kv1.5), leading to the idea that σ1 receptors are auxiliary subunits. σ1 receptors apparently co-localize with IP3 receptors on the endoplasmic reticulum where they may be involved in preventing endoplasmic reticulum stress in neurodegenerative diseases. Also, σ1 receptors have been shown to appear in galactoceramide enriched domains at the endoplasmic reticulum of mature oligodendrocytes. The wide scope and effect of ligand binding on σ1 receptors has led some to believe that σ1 receptors are intracellular signal transduction amplifiers.

Recently, σ1R has been implicated in autophagosome formation and maturation. Autophagy is a broad homeostatic, metabolic, cytoplasmic quality control, and metabolic process affecting many functions in the cell. σ1R is targeted by the nsp6 protein of SARS-CoV-2 to inhibit autophagosome formation as a process competing with the coronavirus for cellular endomembranes that the virus needs for its own replication. This along with the observed beneficial effects of sigma-1 receptor agonist and SSRI fluvoxamine in patients with SARS-COV-2 infection has led to the hypothesis that the sigma-1 receptor could be a target for the treatment of SARS-COV-2.

Pharmacology

The σ1 receptor is defined by its unique pharmacological profile. In 1976 Martin reported that the effects of N-allylnormetazocine (SKF-10,047) could not be due to activity at the μ and κ receptors (named from the first letter of their selective ligands morphine and ketazocine, respectively) and a new type of opioid receptor was proposed; σ (from the first letter of SKF-10,047). The opioid classification was eventually dropped however resulting from it not possessing the canonical opioid G-protein coupled receptor structure and the receptor was later referred to as simply the σ1 receptor. It was found to have affinity for the (+)-stereoisomers of several benzomorphans (e.g., (+)-pentazocine and (+)-cyclazocine), as well as various structurally and pharmacologically distinct psychoactive chemicals such as haloperidol (which irreversibly blocks this receptor) and cocaine, and neuroactive steroids like progesterone. Pharmacological studies with σ1 agonists often follow a bell-shaped dose-response curve. Thus care should be taken when designing experiments and choosing doses of ligands.

Ligands

The following ligands have high affinity for the σ1 receptor and possess high binding selectivity over the subtype σ2:

Agonists

• Amantadine
• Amitriptyline
• Blarcamesine
• Citalopram
• Cocaine
• Cutamesine
• Dextromethorphan
• Dimethoxanate
• Dimethyltryptamine
• Dipentylammonium chloride
• Donepezil
• Fabomotizole
• Fluoxetine
• Fluvoxamine
• L-687,384
• Methamphetamine
• Opipramol
• (+)-Pentazocine (the "unnatural" enantiomer, which lacks affinity for the μ-opioid and κ-opioid receptors.)
• Pipazetate
• Pitolisant
• PRE-084

Antagonists

• BD 1047
• LMH-2
• FTC-146
• Sertraline
• S1RA (E-52862)
• NE-100
• WQ-1
• 1-benzyl-6′-methoxy-6′,7′-dihydrospiro[piperidine-4,4′-thieno[3.2-c]pyran]: putative antagonist, selective against 5-HT1A, 5-HT6, 5-HT7, α1A and α2 adrenergic, and NMDA receptors

Positive allosteric modulators (PAMs)

• Methylphenylpiracetam
• SOMCL-668

Uncategorized

• Clorgiline
• D-Deprenyl
• PD 144418
• RHL-033
• Selegiline
• 4-IPBS
• Spipethiane
• (−)-(S)-4-methyl-1-[2-(4-chlorophenoxy)-1-methylethyl]piperidine
• 1'-[(4-fluorophenyl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]
• 1'-benzyl-6-methoxy-1-phenyl-spiro[6H-furo[3,4-c]pyrazole-4,4'-piperidine]
• 3-[[1-[(4-chlorophenyl)methyl]-4-piperidyl]methyl]-1,3-benzoxazol-2-one: very high affinity and subtype selectivity

Agents exist that have high σ1 affinity but either lack subtype selectivity or have high affinity at other binding sites, thus being more or less dirty/multifunctional, like haloperidol. Furthermore, there is a wide range of agents with an at least moderate σ1 involvement in their binding profile.

Clinical significance

Mutations in the SIGMAR1 gene have been associated with distal spinal muscular atrophy type 2.

There has been much interest in the sigma-1 receptor and its role in age-related neurodegenerative diseases such as Alzheimer's disease. During healthy ageing, the density of sigma-1 receptors has been seen to increase. However, in diseases such as Alzheimer's disease, there appears to be a reduction in sigma-1 receptor expression. It has been suggested that targeting the sigma-1 receptor along with other receptors could increase neuron survival and function in neurodegenerative disease. The activation of autophagy has also been suggested as a downstream mechanism linked to sigma-1 receptor activation.

As a drug target

(Sig-1R) has emerged as a promising therapeutic strategy across multiple neurological, psychiatric, and degenerative conditions. The receptor's role as a molecular chaperone at the endoplasmic reticulum (ER)-mitochondria interface and its modulation of calcium signaling, neurotransmitter systems, and cellular stress responses underpin its therapeutic potential.

Sig-1R ligands show efficacy in preclinical models of depression, anxiety, and schizophrenia. Antidepressants like fluvoxamine and Amitriptyline act partly through Sig-1R agonism, enhancing synaptic plasticity and restoring excitatory/inhibitory balance. Clinical trials with selective agonists (e.g., SA4503, pridopidine) have demonstrated mixed results, but the receptor remains a focus for developing fast-acting antidepressants.

In amyotrophic lateral sclerosis (ALS), Sig-1R agonists (PRE-084, SA4503) improve motor function and motoneuron survival in animal models by modulating ER stress and autophagy. Similarly, Sig-1R activation shows neuroprotective effects in Alzheimer's and Parkinson's models, potentially slowing disease progression.

Despite setbacks in clinical trials (e.g., igmesine for depression), the receptor's broad regulatory roles continue to drive drug discovery, with candidates like ANAVEX2-73 and T-817MA in development for cognitive disorders.

Knockout mice

σ1 receptor knockout mice were created in 2003 to study the effects of endogenous DMT. Strangely, the mice demonstrated no overt phenotype. As expected, however, they did lack locomotor response to the σ ligand (+)-SKF-10,047 and displayed reduced response to formalin induced pain. Speculation has focused on the ability of other receptors in the σ family (e.g., σ2, with similar binding properties) to compensate for the lack of σ1 receptor.

References

57. Déciga-Campos M, Melo-Hernández LA, Torres-Gómez H, Wünsch B, Schepmann D, González-Trujano ME, Espinosa-Juárez J, López-Muñoz FJ, Navarrete-Vázquez G. Design and synthesis of N‑(benzylpiperidinyl)‑4‑fluorobenzamide: A haloperidol analog that reduces neuropathic nociception via σ1 receptor antagonism. Life Sci. 2020 Mar 15;245:117348. doi: 10.1016/j.lfs.2020.117348. Epub 2020 Jan 23. PMID 31981633.

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