Steroid Binding at σ-"Opioid" Receptors

Schwarz, S.; Pohl, Peter; Zhou, Guanglu

doi:10.1126/science.2556797

Cited by 49 publications

(25 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, their affinities for this receptor appear to be too low for them to be endogenous ligands. The physiological levels of progesterone during pregnancy can reach up to 400 nM; however, only 2% of this is free to pass the blood-brain barrier (Pardridge et al, 1988;Schwarz et al, 1989), resulting in only approximately 8 nM free progesterone that is able to interact with sigma-1 receptors in the CNS (Schwarz et al, 1989). More recently, N,Ndimethyltryptamine (DMT) has been proposed as the endogenous ligand (Fontanilla et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Antagonists show GTP‐sensitive high‐affinity binding to the sigma‐1 receptor

Brimson

Brown

Safrany

2011

British J Pharmacology

View full text Add to dashboard Cite

BACKGROUND AND PURPOSESigma-1 receptors are atypical receptors with potentially two transmembrane domains. Antagonists require doses significantly higher than their published affinities to have biological effects. We have reassessed the binding characteristics of these ligands and found antagonists bind to high-and low-affinity states not distinguished by agonists. EXPERIMENTAL APPROACHThe affinities of sigma-1 receptor ligands was assessed using radioligand saturation and competition binding of [ 3 H]-(+)-pentazocine to permeabilized MDA-MB-468 cells. This was compared with the effect of ligands on metabolic activity using an MTS-based assay and calcium signalling using cells loaded with the calcium dye, Fura-2. KEY RESULTSSigma-1 receptor antagonists, but not agonists, show GTP-and suramin-sensitive high-affinity binding. Functional responses (calcium signalling and metabolic activity), while associated with sigma-1 receptor binding, required binding to an unidentified, low-affinity target. CONCLUSIONS AND IMPLICATIONSSigma-1 receptors are coupled to G proteins. This interaction is only observed when analysing antagonist binding. The identity of the G protein remains to be resolved. The concept of agonist and antagonist at the sigma-1 receptor needs to be revisited. Abbreviations(+)-3-PPP, (+)-3-(3-hydroxyphenyl)-N-1-(propyl)piperidine; [Ca 2+ ], free concentration of Ca 2+ ions; DMT, N,Ndimethyltryptamine; IPAG, 1-(4-iodophenyl)-3-(2-adamantyl)guanidine; SKF-10047, N-allylnormetazocine IntroductionThe search for understanding of the sigma-1 receptor has been a long, mysterious and as yet incomplete journey. The receptor has mostly been studied within the CNS. However, more recent work over the past decade has shown the receptor to be abundant in neuronal, and non-neuronal tissues (Vilner et al., 1995) leading to its study in cancer biology (Spruce et al., 2004).The sigma receptor was proposed as a novel fourth opioid receptor in 1976 to account for the behavioural effects of N-allylnormetazocine (SKF-10047), which could not be accounted for by the m (morphine) or k (ketocyclazocine) receptors (Martin et al., 1976). SKF-10047 was defined as an agonist as it raised pulse and respiration rates, as well as body temperature and caused dilatation of pupils in beagles. Interestingly, m-receptor agonists lowered pulse and respiration rates, as well as body temperature and produced classic BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2011 772 British Journal of Pharmacology (2011) 164 772-780The Authors British Journal of Pharmacology © 2011 The British Pharmacological Society pinpoint pupils. Sigma-1 receptor antagonists were defined as agents that were able to prevent these responses. Later studies (e.g. Spruce et al., 2004) suggested that biochemically, agonists do not cause activation of the receptor but can block the effects of antagonists which do. More recently, data obtained using mice in which the sigma-1 receptor has been knocked out further cloud the picture; expression o...

show abstract

Section: Introductionmentioning

confidence: 99%

Antagonists show GTP‐sensitive high‐affinity binding to the sigma‐1 receptor

Brimson

Brown

Safrany

2011

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…This remains however controversial as the affinity of progesterone for sigma receptors does not appear very high for an endogenous ligand. Indeed, Schwarz et al (23) argued that the concentration of endogenous progesterone, specifically the free serum concentration, was insufficient to occupy the sigma receptors in the brain, even during later pregnancy, when progesterone levels are at their highest. However, there are data suggesting that progesterone binds to sigma receptors under physiological conditions.…”

Section: Potential Endogenous Ligands For Sigma Receptorsmentioning

confidence: 99%

The Role of Sigma Receptors in Depression

2005

View full text Add to dashboard Cite

Abstract. Behavioral models used to test potential antidepressants have shown that ligands that bind to sigma receptors possess "antidepressant-like" properties. The focus of this review is to discuss the literature concerning sigma receptors and their ligands, with respect to their antidepressants properties. In addition to the behavioral data, we discuss electrophysiological and biochemical models demonstrating sigma receptors' ability to modulate important factors in the pathophysiology of depression and / or the mechanisms of action of antidepressants such as the serotonergic neurotransmission in the dorsal raphe nucleus (DRN) and the glutamatergic transmission in the hippocampus. We also discuss the significance of these two systems in the mechanism of action of antidepressants. Sigma ligands have potential as antidepressant medications with a fast onset of action as they produce a rapid modulation of the serotonergic system in the DRN and the glutamatergic transmission in the hippocampus. As these effects of sigma ligands may produce antidepressant properties by completely novel mechanisms of action, they may provide an alternative to the antidepressants currently available and may prove to be beneficial for treatment-resistant depressed patients.

show abstract

“…Haloperidol, which also displays high affinity for a binding sites (19,20) but not spiperone, another butyrophenone devoid of such affinity (21,22), prevented the effects of JO-1784 and DTG (3). Pregnenolone (23) and splenocyte plasma membranes (24). However *To whom reprint requests should be sent at the t address.…”

mentioning

confidence: 99%

Neurosteroids, via sigma receptors, modulate the [3H]norepinephrine release evoked by N-methyl-D-aspartate in the rat hippocampus.

Monnet

Mahé

Röbel

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

396

230

View full text Add to dashboard Cite

N-Methyl-D-aspartate (NMDA, 200 pzM) evokes the release of [3H]norepinephrine ([3H]NE) from preloaded hippocampal slices. This effect is potentiated by dehydroepiandrosterone sulfate (DHEA S), whereas it is inhibited by pregnenolone sulfate (PREG S) and the highaffinity r inverse agonist 1,3-di(2-tolyl)guanidine, at concentrations of .100 nM. Neither 3a-hydroxy-5a-pregnan-20-one nor its sulfate ester modified NMDA-evoked [3H] NE overflow. Eighty-four female Sprague-Dawley rats (180-225 g), purchased from Iffa Credo, were kept at 21°C on a 12 hr:12 hr light/dark cycle with free access to water and Purina chow. At least 4 weeks prior to the release experiments, rats were anesthetized under ether and bilateral ovariectomy was carried out by lateral access. In a subgroup of 16 rats, anesthetized with chloral hydrate (400 mg/kg, i.p.) 3-11 days prior to the experiments, PTX (1 ,g/2 ,ul of physiological saline) was injected (using a 10-uAl Hamilton syringe) bilaterally into the dorsal hippocampus at A: 4.5, L: 4, and D: 4, according to the atlas of Paxinos and Watson (25) as described (3). Twelve control rats received an equal volume of the vehicle. When appropriate, the rats were killed by decapitation and their brains were rapidly dissected. Coronal slices (0.4-mm thick) of the hippocampus were prepared with a McIlwain tissue chopper. The slices were incubated in Krebs' solution containing[3H]NE (0.1 ,uM) and bubbled with a mixture of 95% 02/5% CO2 at 37°C for 30 min. The composition of the Krebs' solution (in mM) was NaCl 118, KCl 4.7, CaCl2 1.3, MgCl2 1.2, NaH2PO4 1, NaHCO3 25, glucose 11.1, Na2EDTA 0.04, and ascorbic acid 0.06. At the end of the incubation period, each glass chamber received two slices that were superfused continuously at a rate of 0.5 ml/min with oxygenated Mg2+-free Krebs' solution at 37°C for 68 min. As indicated in Results, one steroid and/or one of the cr ligands DTG, haloperidol, BD-1063, or spiperone were added in Mg2+-free Krebs' solution throughout the superfusion period. The prototypic a-ligand DTG was chosen since it acts on both a-i and o'2 receptors (3, 26). The universal o-antagonist haloperidol also binds to dopaminergic, serotoninergic, adrenergic, and cholinergic sites Abbreviations: 3a,5a-THP, 3a-hydroxy-Sa-pregnan-20-one; CNS, central nervous system; DHEA, dehydroepiandrosterone; DTG, 1,3-di(2-tolyl)guanidine; Gi/o protein, guanine nucleotide-binding pro-

show abstract

Steroid Binding at σ-"Opioid" Receptors

Cited by 49 publications

References 63 publications

Antagonists show GTP‐sensitive high‐affinity binding to the sigma‐1 receptor

Antagonists show GTP‐sensitive high‐affinity binding to the sigma‐1 receptor

The Role of Sigma Receptors in Depression

Neurosteroids, via sigma receptors, modulate the [3H]norepinephrine release evoked by N-methyl-D-aspartate in the rat hippocampus.

Contact Info

Product

Resources

About