The sigma-1 receptor is widely distributed in the central nervous system and periphery. Originally mischaracterized as an opioid receptor, the sigma-1 receptor binds a vast number of synthetic compounds but does not bind opioid peptides; it is currently considered an orphan receptor. The sigma-1 receptor pharmacophore includes an alkylamine core, also found in the endogenous compound N,N-dimethyltryptamine (DMT). DMT acts as a hallucinogen, but its receptor target has been unclear. DMT bound to sigma-1 receptors and inhibited voltage-gated sodium ion (Na+) channels in both native cardiac myocytes and heterologous cells that express sigma-1 receptors. DMT induced hypermobility in wild-type mice but not in sigma-1 receptor knockout mice. These biochemical, physiological, and behavioral experiments indicate that DMT is an endogenous agonist for the sigma-1 receptor.

Receptors, once considered a class of opioid receptors, are now regarded as a unique class of receptors that contain binding sites for a wide range of ligands, including the drug 1-N(2Ј,6Ј-dimethylmorpholino)3-(4-t-butylpropylamine) (fenpropimorph), a yeast sterol isomerase inhibitor. Because fenpropimorph has high-binding affinity to the -1 receptor, we have synthesized a series of fenpropimorph-like derivatives with varying phenyl ring substituents and have characterized their binding affinities to the -1 receptor. In addition, we have synthesized a carrier-free, radioiodinated fenpropimorph-like photoaffinity label, 1-N-(2Ј,6Ј-dimethyl-morpholino)-3-(4-azido- The receptor is a unique receptor that, for the past 30 years, has been persistently enigmatic. receptors were initially proposed to be subtypes of opioid receptors based on work performed by Martin and colleagues (1976) to study the actions of antipsychotic drugs. In these experiments, they proposed the existence of a -opioid receptor based on the psychomimetic effects of SKF-10047, which could not be explained by -or -opioid receptors (Martin et al., 1976). This hypothesis, however, was later refuted when the receptor was shown to be insensitive to naloxone, a common opioid receptor antagonist (Iwamoto, 1981;Su, 1982;Vaupel, 1983). As a result, receptors were reclassified as unique nonopioid and nonphencyclidine binding sites present in the central nervous system and peripheral organs that are distinct from other known neurotransmitter or hormone receptors (Quirion et al., 1992).To date, two subtypes of the receptor have been identified, the -1 and -2 receptors, which are distinguishable by their pharmacology, function, and molecular mass. The -1 receptor was first cloned from guinea pig liver in 1996 and subsequently from other sources, including human placental choriocarcinoma cells (Kekuda et al., 1996), human brain (Prasad et al., 1998), rat brain (Seth et al., 1998;Mei and Pasternak, 2001), and mouse brain (Pan et al., 1998). The -2 receptor, however, has yet to be cloned. The -1 receptor has 223 amino acids and shares 30% identity and 67% similarity with a yeast sterol C8 -C7 isomerase, which is involved in cholesterol synthesis (Moebius et al., 1997). Unlike this yeast sterol isomerase, however, the -1 receptor does not have any sterol isomerase activity , and it shares no sequence homology with any known mammalian proteins, including the mammalian C8 -C7 sterol isomerase. This work was supported by the National Institutes of Health grant R01-MH065503 (to A.E.R.).Article, publication date, and citation information can be found at

Sigma-1 receptors are associated with Alzheimer's disease, major depressive disorders, and schizophrenia. These receptors show progrowth/antiapoptotic properties via their chaperoning functions to counteract ER (endoplasmic reticulum) stress, to block neurodegeneration, and to regulate neuritogenesis. The sigma-1 receptor knock out mouse offered an opportunity to assess possible mechanisms by which the Sigma-1 receptor modulates cellular oxidative stress. Nuclear magnetic resonance (NMR) metabolomic screening of the WT (wild type) and sigma-1 KO (knockout) livers was performed to investigate major changes in metabolites that are linked to oxidative stress. Significant changes in protein levels were also identified by two-dimensional (2D) gel electrophoresis and mass spectrometry. Increased levels of the antioxidant protein peroxiredoxin 6 (Prdx6), and the ER chaperone BiP (GRP78) compared to WT littermates were detected. Oxidative stress was measured in WT and sigma-1 KO mouse liver homogenates, in primary hepatocytes and in lung homogenates. Furthermore, sigma-1 receptor mediated activation of the antioxidant response element (ARE) to upregulate NAD(P)H quinone oxidoreductase 1 (NQO1) and superoxide dismutase 1 (SOD1) mRNA expression in COS cells was shown by RT PCR. These novel functions of the sigma-1 receptor were sensitive to well-known sigma ligands via their antagonist/agonist properties.

σ-Receptors are integral membrane proteins that have been implicated in a number of biological functions, many of which involve the modulation of ion channels. A wide range of synthetic ligands activate σ-receptors, but endogenous σ-receptor ligands have proven elusive. One endogenous ligand, dimethyltryptamine (DMT), has been shown to act as a σ-receptor agonist. Progesterone and other steroids bind σ-receptors, but the functional consequences of these interactions are unclear. Here we investigated progesterone binding to σ(1)- and σ(2)-receptors and evaluated its effect on σ-receptor-mediated modulation of voltage-gated Na(+) channels. Progesterone binds both σ-receptor subtypes in liver membranes with comparable affinities and blocks photolabeling of both subtypes in human embryonic kidney 293 cells that stably express the human cardiac Na(+) channel Na(v)1.5. Patch-clamp recording in this cell line tested Na(+) current modulation by the σ-receptor ligands ditolylguanidine, PB28, (+)SKF10047, and DMT. Progesterone inhibited the action of these ligands to varying degrees, and some of these actions were reduced by σ(1)-receptor knockdown with small interfering RNA. Progesterone inhibition of channel modulation by drugs was consistent with stronger antagonism of σ(2)-receptors. By contrast, progesterone inhibition of channel modulation by DMT was consistent with stronger antagonism of σ(1)-receptors. Progesterone binding to σ-receptors blocks σ-receptor-mediated modulation of a voltage-gated ion channel, and this novel membrane action of progesterone may be relevant to changes in brain and cardiovascular function during endocrine transitions.