Sigma-1 receptor
The sigma-1 receptor (1R), 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 1 receptor is encoded by the SIGMAR1 gene.
The 1 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 1 receptor.
An endogenous ligand for the 1 receptor has yet to be conclusively identified, but tryptaminergic trace amines, as well as neuroactive steroids such as dehydroepiandrosterone (DHEA) and pregnenolone all activate the receptor.

# Characteristics
The 1 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  and  receptors (named from the first letter of their selective ligands morphine and ketazocine, respectively) and a new type of opioid receptor was proposed;  (from the first letter of SKF-10,047).  Ligands acting at this new opioid receptor were blocked by the classical opioid antagonists naloxone and naltrexone. 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 1 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.

# Structure
The mammalian 1 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  C 8-C7 sterol  isomerase in the ergosterol biosynthetic pathway. Hydropathy analysis of the 1 receptor indicates three hydrophobic regions. A crystal structure of the 1 receptor was published in 2016.

# Functions
A variety of specific physiological functions have been attributed to the 1 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 1 receptors have been linked circumstantially to a wide variety of signal transduction pathways. Links between 1 receptors and G-proteins have been suggested such as  1 receptor antagonists showing GTP-sensitive high-affinity binding; there is also, however, some evidence against a G-protein coupled hypothesis. The 1 receptor has been shown to appear in a complex with voltage gated K+ channels (Kv1.4 and Kv1.5), leading to the idea that 1 receptors are auxiliary subunits. 1 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, 1 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 1 receptors has led some to believe that 1 receptors are intracellular signal transduction amplifiers.

# Knockout mice
1 receptor knockout mice were created in 2009 to study the effects of endogenous DMT. Strangely, the mice demonstrated no overt phenotype. As expected, however, they did lack locomotor response to the  ligand (+)-SKF-10,047 and displayed reduced response to formalin induced pain. Speculation has focused on the ability of other receptors in the  family (e.g., 2, with similar binding properties) to compensate for the lack of 1 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 1 receptor and possess high binding selectivity over the subtype 2:
Agonists:
- PRE-084
- Anavex 2-73
- Fluvoxamine
- Amitriptyline
- L-687,384
- SA-4503
- Dextromethorphan
- Dimethyltryptamine
- (+)-pentazocine (the "unnatural" enantiomer, which lacks affinity for the -opioid and -opioid receptors.
Antagonists:
- Sertraline
- S1RA
- 1-benzyl-6-methoxy-6,7-dihydrospiropyran]: putative antagonist, selective against 5-HT1A, 5-HT6, 5-HT7, 1A and 2 adrenergic, and NMDA receptors
- NE-100
Positive allosteric modulators (PAMs):
- Methylphenylpiracetam
- SOMCL-668
Uncategorized:
- 4-IPBS
- PD 144418
- spipethiane
- RHL-033
- 3--4-piperidyl]methyl]-1,3-benzoxazol-2-one: very high affinity and subtype selectivity
- 1'-spiro
- 1'-benzyl-6-methoxy-1-phenyl-spiropyrazole-4,4'-piperidine]
- ()-(S)-4-methyl-1-piperidine
Agents exist that have high 1 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 1 involvement in their binding profile.