Sigma receptor

The sigma receptors σ1 and σ2 bind to ligands such as 4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine), SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. They are named by pharmacological similarities, and 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 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. Activation of σ–receptors by an agonist ligand may induce hallucinogenic effects and also may be responsible for the paradoxical convulsions sometimes seen in opiate overdose. Drugs known to be σ–agonists include cocaine, morphine/diacetylmorphine, opipramol, PCP, fluvoxamine, methamphetamine, dextromethorphan, and the herbal antidepressant 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. Behavioral reactions to σ–agonists are rather heterogeneous: some individuals find σ–receptor agonists euphoric with significant anti-depressive effects. Other individuals, however, experience dysphoria and often report feelings of malaise or anxiety.
In 2007 selective σ–receptor agonists were shown to produce antidepressant-like effects in mice.