Sigma-1 receptor

The sigma-1 receptor (σ1R), one of two is_associated_with::sigma receptor subtypes, is a chaperone protein at the is_associated_with::Endoplasmic reticulum (ER) that modulates is_associated_with::calcium signaling through the is_associated_with::IP3 receptor. In humans, the σ1 receptor is encoded by the SIGMAR1 is_associated_with::gene.

The σ1 receptor is a is_associated_with::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 myriad phenomena, including cardiovascular function, is_associated_with::schizophrenia, is_associated_with::clinical depression, the effects of is_associated_with::cocaine abuse, and cancer. Much is known about the binding affinity of hundreds of synthetic compounds to the σ1 receptor.

An endogenous ligand for the σ1 receptor has yet to be conclusively identified, but is_associated_with::tryptaminergic is_associated_with::trace amines, as well as is_associated_with::neuroactive steroids such as is_associated_with::dehydroepiandrosterone (DHEA) and is_associated_with::pregnenolone all activate the receptor.

Characteristics
The σ1 receptor is defined by its unique pharmacological profile. In 1976 Martin reported that the effects of is_associated_with::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 is_associated_with::morphine and is_associated_with::ketazocine, respectively) and a new type of is_associated_with::opioid receptor was proposed; σ (from the first letter of SKF-10,047). However, ligands acting at this new “opioid” receptor were not blocked by the classical opioid antagonists is_associated_with::naloxone and is_associated_with::naltrexone. Consequently, the opioid classification was eventually dropped and the receptor was later termed the σ1 receptor. It was found to have affinity for the (+)-is_associated_with::stereoisomers of several is_associated_with::benzomorphans (e.g., (+)-is_associated_with::pentazocine and (+)-is_associated_with::cyclazocine), various structurally and pharmacologically distinct psychoactive chemicals such as is_associated_with::haloperidol and is_associated_with::cocaine, and is_associated_with::neuroactive steroids like is_associated_with::progesterone.

Structure
The mammalian σ1 receptor  was  purified with the aid of  radiolabelled pentazocine  and azidopamil as reversible and photo affinity probes, respectively, from guinea pig liver, cloned and  expressed. The receptor is an integral membrane protein with 223 is_associated_with::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  is_associated_with::isomerase in the is_associated_with::ergosterol biosynthetic pathway. Hydropathy analysis of the σ1 receptor indicates three hydrophobic regions. A crystal structure of the σ1 receptor is unavailable.

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 is_associated_with::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 σ1 receptor 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 (Kv1.4 and Kv1.5), leading to the idea that σ1 receptors are auxiliary subunits. σ1 receptors apparently co-localize with IP3 receptors on the is_associated_with::endoplasmic reticulum. Also, σ1 receptors have been shown to appear in galactoceramide enriched domains at the endoplasmic reticulum of mature is_associated_with::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 (e.g., σ2, with similar binding properties) to compensate for the lack of σ1 receptor.

Ligands
Today, ligands are known which have high affinity for the σ1 receptor and possess high binding selectivity over the subtype σ2:

Agonists:
 * is_associated_with::PRE-084
 * is_associated_with::Anavex 2-73
 * is_associated_with::fluvoxamine
 * is_associated_with::sertraline
 * is_associated_with::amitriptyline
 * is_associated_with::Dextromethorphan
 * is_associated_with::Dimethyltryptamine
 * (+)-pentazocine ("unnatural" isomer of is_associated_with::pentazocine which lacks affinity for the μ-opioid and κ-opioid receptors.

Antagonists:
 * 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

PAMs:
 * is_associated_with::E1R

Uncategorized:
 * is_associated_with::4-IPBS
 * is_associated_with::NE-100
 * is_associated_with::L-687,384
 * is_associated_with::PD 144418
 * is_associated_with::SA-4503
 * is_associated_with::spipethiane
 * is_associated_with::RHL-033
 * is_associated_with::S1RA
 * 3-[[1-[(4-chlorophenyl)methyl]-4-piperidyl]methyl]-1,3-benzoxazol-2-one: very high affinity and subtype selectivity
 * 1'-[(4-fluorophenyl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]
 * 1'-benzyl-6-methoxy-1-phenyl-spiro[6H-furo[3,4-c]pyrazole-4,4'-piperidine]
 * (−)-(S)-4-methyl-1-[2-(4-chlorophenoxy)-1-methylethyl]piperidine

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 is_associated_with::haloperidol. Furthermore, there is a wide range of agents with an at least moderate σ1 involvement in their binding profile.