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).^[13] 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 and cocaine, and neuroactive steroids like progesterone.^[14] Pharmacological studies with σ₁ agonists often follow a bell-shaped dose-response curve.^[15] Thus care should be taken when designing experiments and choosing doses of ligands.

The mammalian σ₁ receptor is an integral membrane protein with 223 amino acids.^[16] It shows no homology to other mammalian proteins but strikingly shares 30% sequence identity and 69% similarity with the ERG2 gene product of yeast, which is a C8-C7 sterol isomerase in the ergosterol biosynthetic pathway. Hydropathy analysis of the σ₁ receptor indicates three hydrophobic regions.^[17] A crystal structure of the σ₁ receptor was published in 2016.^[18]

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.^[19] 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;^[20] there is also, however, some evidence against a G-protein coupled hypothesis.^[21] The σ₁ receptor has been shown to appear in a complex with voltage gated K⁺ channels (K_v1.4 and K_v1.5), leading to the idea that σ₁ receptors are auxiliary subunits.^[22] σ₁ receptors apparently co-localize with IP₃ receptors on the endoplasmic reticulum^[23] where they may be involved in preventing endoplasmic reticulum stress in neurodegenerative diseases.^[24] Also, σ₁ receptors have been shown to appear in galactoceramide enriched domains at the endoplasmic reticulum of mature oligodendrocytes.^[25] The wide scope and effect of ligand binding on σ₁ receptors has led some to believe that σ₁ receptors are intracellular signal transduction amplifiers.^[14]

Recently, σ₁R has been implicated in autophagosome formation ^[26] and maturation.^[27] Autophagy is a broad homeostatic, metabolic, cytoplasmic quality control, and metabolic process affecting many functions in the cell.^[28] σ₁R is targeted by the nsp6 protein of SARS-CoV-2^[29][26] to inhibit autophagosome formation ^[26] 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^[30] has led to the hypothesis that the sigma-1 receptor could be a target for the treatment of SARS-COV-2.^[31]

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 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.^[15] The activation of autophagy has also been suggested as a downstream mechanism linked to sigma-1 receptor activation.^[32]

σ₁ receptor knockout mice were created in 2003 to study the effects of endogenous DMT. Strangely, the mice demonstrated no overt phenotype.^[33] 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.^[33]

Mutations in the SIGMAR1 gene have been associated with distal spinal muscular atrophy type 2.^[34]

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

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.^[44][45]

• Sigma-2 receptor

• sigma-1+receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• SIGMAR1 human gene location in the UCSC Genome Browser.
• SIGMAR1 human gene details in the UCSC Genome Browser.