Sigma-1 receptor
The sigma-1 receptor (σR), one of two sigma receptor subtypes, is a chaperone protein at the endoplasmic reticulum (ER) that modulates calcium signaling through the IP3 receptor. In humans, the σ receptor is encoded by the "SIGMAR1" gene. The σ receptor is a transmembrane protein expressed in many different tissue types. It is particularly concentrated in certain regions of the central nervous system. It has been implicated in several phenomena, including cardiovascular function, schizophrenia, clinical depression, the effects of cocaine abuse, and cancer. Much is known about the binding affinity of hundreds of synthetic compounds to the σ  receptor. An endogenous ligand for the σ receptor has yet to be conclusively identified, but tryptaminergic trace amines and neuroactive steroids have been found to activate the receptor. Especially progesterone, but also testosterone, pregnenolone sulfate, and dehydroepiandrosterone sulfate (DHEA-S) bind to the σ receptor. Characteristics. The σ 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 σ 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. Pharmacological studies with σ agonists often follow a bell-shaped dose-response curve. Thus care should be taken when designing experiments  and chosing doses of ligands. Structure. The mammalian σ receptor is an integral membrane protein with 223 amino acids. 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 σ receptor indicates three hydrophobic regions. A crystal structure of the σ receptor was published in 2016. Functions. A variety of specific physiological functions have been attributed to the σ receptor. Chief among these are modulation of Ca release, modulation of  cardiac myocyte contractility, and inhibition of voltage gated K channels. The reasons for these effects are not well understood, even though σ receptors have been linked circumstantially to a wide variety of signal transduction pathways. Links between σ receptors and G-proteins have been suggested such as σ receptor antagonists showing GTP-sensitive high-affinity binding; there is also, however, some evidence against a G-protein coupled hypothesis. The σ receptor has been shown to appear in a complex with voltage gated K channels (K1.4 and K1.5), leading to the idea that σ receptors are auxiliary subunits. σ receptors apparently  co-localize with IP receptors on the endoplasmic reticulum where they may be involved in preventing endoplasmic reticulum stress in neurodegenerative diseases. Also, σ 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 σ receptors has led some to believe that σ receptors are intracellular signal transduction amplifiers. Recently, σR 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. σR 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 they hypothesis that the sigma-1 receptor could be a target for the treatment of SARS-COV-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 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. Knockout mice. σ 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.", σ, with similar binding properties) to compensate for the lack of σ receptor. Clinical significance. Mutations in sigma-1 receptor have been associated with distal spinal muscular atrophy type 2. Ligands. The following ligands have high affinity for the σ receptor and possess high binding selectivity over the subtype σ: Agonists: Antagonists: Positive allosteric modulators (PAMs): Uncategorized: Agents exist that have high σ affinity but either lack subtype selectivity or have high affinity at other binding sites, thus being more or less dirty drug|dirty /multifunctional, like  haloperidol . Furthermore, there is a wide range of agents with an at least moderate σ involvement in their binding profile.