Sigma-1 receptor

Sigma non-opioid intracellular receptor 1
Identifiers
Symbols	SIGMAR1 ; ALS16; OPRS1; SIG-1R; SR-BP; SR-BP1; SRBP; hSigmaR1; sigma1R
External IDs	OMIM: 601978 MGI: 1195268 HomoloGene: 39965 IUPHAR: 2552 ChEMBL: 287 GeneCards: SIGMAR1 Gene
Gene ontology Molecular function • opioid receptor activity • drug binding Cellular component • nuclear envelope • nuclear inner membrane • nuclear outer membrane • endoplasmic reticulum membrane • lipid particle • integral component of plasma membrane • integral component of membrane • cell junction • growth cone Biological process • lipid transport • nervous system development • opioid receptor signaling pathway • regulation of neuron apoptotic process Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	10280	18391
Ensembl	ENSG00000147955	ENSMUSG00000036078
UniProt	Q99720	O55242
RefSeq (mRNA)	NM_001282205	NM_001286538
RefSeq (protein)	NP_001269134	NP_001273467
Location (UCSC)	Chr 9: 34.63 – 34.64 Mb	Chr 4: 41.74 – 41.76 Mb
PubMed search	[1]	[2]

The sigma-1 receptor (σ₁R), 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 σ₁ receptor is encoded by the SIGMAR1 gene.

The σ₁ 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 myriad 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 σ₁ receptor.

An endogenous ligand for the σ₁ 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 σ₁ 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). However, ligands acting at this new “opioid” receptor were not blocked by the classical opioid antagonists naloxone and 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 (+)-stereoisomers of several benzomorphans (e.g., (+)-pentazocine and (+)-cyclazocine), various structurally and pharmacologically distinct psychoactive chemicals such as haloperidol and cocaine, and neuroactive steroids like 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 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 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 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 (K_v1.4 and K_v1.5), leading to the idea that σ₁ receptors are auxiliary subunits. σ₁ receptors apparently co-localize with IP₃ receptors on the endoplasmic reticulum. 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 (e.g., σ₂, with similar binding properties) to compensate for the lack of σ₁ 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 σ₁ receptor and possess high binding selectivity over the subtype σ₂:

Agonists:

• PRE-084
• Anavex 2-73
• fluvoxamine
• sertraline
• amitriptyline
• Dextromethorphan
• Dimethyltryptamine
• (+)-pentazocine ("unnatural" isomer of 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-HT_1A, 5-HT₆, 5-HT₇, α_1A and α₂ adrenergic, and NMDA receptors

Positive allosteric modulators (PAMs):

• Methylphenylpiracetam

Uncategorized:

• 4-IPBS
• NE-100
• L-687,384
• PD 144418
• SA-4503
• spipethiane
• RHL-033
• 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 haloperidol. Furthermore, there is a wide range of agents with an at least moderate σ₁ involvement in their binding profile.

See also

• Sigma receptor
• Sigma-2 receptor

External links

• sigma-1 receptor at the US National Library of Medicine Medical Subject Headings (MeSH)
• SIGMAR1 human gene location in the UCSC Genome Browser.
• SIGMAR1 human gene details in the UCSC Genome Browser.