The σ1 receptor is atransmembrane protein expressed in many different tissue types. It is particularly concentrated in certain regions of the central nervous system.[8] It has been implicated in several phenomena, including cardiovascular function,schizophrenia,clinical depression, the effects ofcocaine abuse,bipolar disorder, and cancer.[9][10] Much is known about the binding affinity of hundreds of synthetic compounds to the σ1 receptor.
The mammalian σ1 receptor is an integral membrane protein composed of 223amino acids.[13] 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 sterolisomerase involved in theergosterol biosynthesis pathway. Hydropathy analysis reveals threehydrophobic regions within the σ1 receptor.[14] A crystal structure of the human σ1 receptor was first published in 2016.[15]
The sigma-1 receptor is a small, unique integral membrane protein predominantly localized to theendoplasmic 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 singleN-terminal transmembrane helix, acupin-likeβ-barrel domain that contains the ligand-binding site, and aC-terminal V-shaped two-helix bundle that functions as a lid over this pocket.[16][17] The ligand-binding pocket is highly conserved and predominantlyhydrophobic, shielded from the aqueous environment. Key residues such as Glu172 and Asp126 play crucial roles in coordinating ligand interactions.[17] 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.[16][17] The receptor's architecture supports its function as a chaperone and modulator of numerous intracellular signaling pathways.[16][17][18]
A variety of specific physiological functions have been attributed to the σ1 receptor. Chief among these are modulation of Ca2+ release, modulation of cardiacmyocyte contractility, and inhibition ofvoltage 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 (Kv1.4 and Kv1.5), leading to the idea that σ1 receptors are auxiliary subunits.[22] σ1 receptors apparently co-localize withIP3 receptors on theendoplasmic 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 matureoligodendrocytes.[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.[26]
Recently, σ1R has been implicated inautophagosome formation[27] and maturation.[28]Autophagy is a broad homeostatic, metabolic, cytoplasmic quality control, and metabolic process affecting many functions in the cell.[29] σ1R is targeted by the nsp6 protein ofSARS-CoV-2[30][27] to inhibit autophagosome formation[27] as a process competing with thecoronavirus for cellularendomembranes 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[31] has led to the hypothesis that the sigma-1 receptor could be a target for the treatment of SARS-COV-2.[32]
The σ1 receptor is defined by its unique pharmacological profile. In 1976 Martin reported that the effects ofN-allylnormetazocine (SKF-10,047) could not be due to activity at the μ and κ receptors (named from the first letter of their selective ligandsmorphine andketazocine, respectively) and a new type ofopioid receptor was proposed; σ (from the first letter of SKF-10,047).[33] 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 severalbenzomorphans (e.g., (+)-pentazocine and (+)-cyclazocine), as well as various structurally and pharmacologically distinct psychoactive chemicals such ashaloperidol (which irreversibly blocks this receptor[34]) andcocaine, andneuroactive steroids likeprogesterone.[26]Pharmacological studies with σ1 agonists often follow a bell-shaped dose-response curve.[35] Thus care should be taken when designing experiments and choosing doses of ligands.
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[39]
3-[[1-[(4-chlorophenyl)methyl]-4-piperidyl]methyl]-1,3-benzoxazol-2-one: very high affinity and subtype selectivity[45]
Agents exist that have high σ1 affinity but either lack subtype selectivity or have high affinity at other binding sites, thus being more or lessdirty/multifunctional, likehaloperidol. Furthermore, there is a wide range of agents with an at least moderate σ1 involvement in their binding profile.[46][47][36]
There has been much interest in the sigma-1 receptor and its role in age-related neurodegenerative diseases such asAlzheimer's disease. During healthy ageing, the density of sigma-1 receptors has been seen to increase. However, in diseases such asAlzheimer'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.[35] The activation of autophagy has also been suggested as a downstream mechanism linked to sigma-1 receptor activation.[49]
(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 ofdepression,anxiety, andschizophrenia. Antidepressants likefluvoxamine andAmitriptyline act partly through Sig-1R agonism, enhancing synaptic plasticity and restoring excitatory/inhibitory balance.[50][51] Clinical trials with selective agonists (e.g.,SA4503,pridopidine) have demonstrated mixed results, but the receptor remains a focus for developing fast-acting antidepressants.[51][52]
Inamyotrophic lateral sclerosis (ALS), Sig-1R agonists (PRE-084, SA4503) improve motor function and motoneuron survival in animal models by modulating ER stress and autophagy.[53][54] Similarly, Sig-1R activation shows neuroprotective effects in Alzheimer's and Parkinson's models, potentially slowing disease progression.[50][52]
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.[52][55]
σ1 receptorknockout mice were created in 2003 to study the effects of endogenousDMT. Strangely, the mice demonstrated no overt phenotype.[56] 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.[56]
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