The σ1 receptor is defined by its unique pharmacological profile. In 1976 Martin reported that the effects of N-allylnormetazocine could not be due to activity at the μ and κ receptors and a new type of opioid receptor was proposed; σ. 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 -pentazocine and, as well as various structurally and pharmacologically distinct psychoactive chemicals such as haloperidol and cocaine, and neuroactive steroids like progesterone.
Structure
The mammalian σ1 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 σ1 receptor indicates three hydrophobic regions. A crystal structure of the σ1 receptor was published in 2016.
Functions
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 σ1receptor 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, 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.
Knockout mice
σ1 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 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 to compensate for the lack of σ1 receptor.
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.
