Sigma receptors (σ-receptors) are protein cell surface receptors that bind ligands such as 4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine), SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. There are two subtypes, sigma-1 receptors (σ1) and sigma-2 receptors (σ2), which are classified as sigma receptors for their pharmacological similarities, even though they are evolutionarily unrelated.
The fungal protein ERG2, a C-8 sterol isomerase, falls into the same protein family as sigma-1. Both localize to the ER membrane, although sigma-1 is also reported to be a cell surface receptor. Sigma-2 is an EXPREA domain protein (citation needed) with a mostly intracellular (ER membrane) localization.
Classification
Because the σ-receptor was originally discovered to be agonized by benzomorphan opioids and antagonized by naltrexone, σ-receptors were originally believed to be a type of opioid receptor. When the σ1 receptor was isolated and cloned, it was found to have no structural similarity to the opioid receptors, but rather showed similarity to fungal proteins involved in sterol synthesis. At this point, they were designated as a separate class of proteins.
Function
The function of these receptors is poorly understood. Drugs known to be σ-agonists include cocaine, morphine/diacetylmorphine, opipramol, PCP, fluvoxamine, methamphetamine, dextromethorphan, and berberine. However, the exact role of σ-receptors is difficult to establish as many σ-agonists also bind to other targets such as the κ-opioid receptor and the NMDA glutamate receptor. In animal experiments, σ-antagonists such as rimcazole were able to block convulsions from cocaine overdose. σ-antagonists are also under investigation for use as antipsychotic medications.
The abundant neurosteroid steroid hormone DHEA is an agonist at sigma receptors and along with pregnenolone could be endogenous agonist ligands; opposed by sigma antagonistic activity from progesterone. Another endogenous ligand, N,N-dimethyltryptamine, was also found to interact with σ1.
Physiologic effects
Physiologic effects when the σ-receptor is activated include hypertonia, tachycardia, tachypnea, antitussive effects, and mydriasis. Some σ-receptor agonists—such as cocaine, a weak σ-agonist—exert convulsant effects in animals.
In 2007 selective σ-receptor agonists were shown to produce antidepressant-like effects in mice.
σ-receptors were also shown to have a role in the regulation of iron/heme homeostasis.
Ligands
Agonists
Choline: 3-MeO-PCP: selective for σ1 subtype, Ki = 42nM 4-PPBP Afobazole: selective for σ1 subtype Allylnormetazocine (SKF-10047) Anavex 2-73 Arketamine BD1031: selective for σ1 subtype BD1052: selective for σ1 subtype Berberine Citalopram Cocaine Dehydroepiandrosterone (DHEA) Dehydroepiandrosterone sulfate (DHEA-S) Dextromethorphan (DXM): relatively selective for σ1 subtype Dextrorphan N,N-Dimethyltryptamine (DMT) Dimemorfan Ditolylguanidine Escitalopram Fluoxetine Fluvoxamine Igmesine Ketamine L-687,384: selective for σ1 subtype Lamotrigine Memantine: selective for σ1 subtype, low affinity Methamphetamine Methylphenidate Noscapine OPC-14523 Opipramol PB-28: selective for σ2 subtype Pentazocine Pentoxyverine: selective for σ1 subtype Phencyclidine (+)-3-PPP PRE-084: selective for σ1 subtype Pregnenolone Pregnenolone sulfate SA 4503: selective for σ1 subtype Siramesine UMB23 UMB82