A proposal for the classification of sigma binding sites

Quirion, Rémi; Bowen, Wayne D.; Itzhak, Yossef; Junien, J.L.; Musacchio, José M.; Rothman, Richard B.; Su, Tsung‐Ping; Tam, S. William; Taylor, Duncan P.

doi:10.1016/0165-6147(92)90030-a

Cited by 723 publications

(594 citation statements)

References 23 publications

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“…Sigma receptors consist of several subtypes that are distinguishable by biochemical and pharmacological means [41]. Among these, the type 1 sigma receptor (σR1) is the best characterized.…”

Section: Introductionmentioning

confidence: 99%

The sigma receptor ligand (+)−pentazocine prevents apoptotic retinal ganglion cell death induced in vitro by homocysteine and glutamate

Martin

Ola

Agarwal

et al. 2004

Molecular Brain Research

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Recent studies demonstrated that the excitotoxic amino acid homocysteine induces apoptotic death of retinal ganglion cells in vivo. In the present study, an in vitro rat retinal ganglion cell culture system was used to analyze the toxicity of acute exposure to high levels of homocysteine, the mechanism of homocysteine-induced toxicity and the usefulness of σR1 ligands as neuroprotectants. When cultured RGC-5 cells were subjected to treatment with 1 mM D, Lhomocysteine, a significant increase in cell death was detected by TUNEL analysis and analysis of activated caspase. When cells were treated with homocysteine-or glutamate in the presence of MK-801, an antagonist of the NMDA receptor, the cell death was inhibited significantly. In contrast, NBQX, an antagonist of the AMPA/Kainate receptor, and nifedipine, a calcium channel blocker, did not prevent the homocysteine-or glutamate-induced cell death. Semi-quantitative RT-PCR and immunocytochemical analysis demonstrated that RGC-5 cells exposed to homocysteine or glutamate express type 1 sigma receptor at levels similar to control cells. Treatment of RGC-5 cells with 3 µM or 10 µM concentrations of the σR1-specific ligand (+)-pentazocine inhibited significantly the apoptotic cell death induced by homocysteine or glutamate. The results suggest that homocysteine is toxic to ganglion cells in vitro, that the toxicity is mediated via NMDA receptor activation, and that the σR1-specific ligand (+)-pentazocine can block the RGC-5 cell death induced by homocysteine and glutamate.

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Section: Introductionmentioning

confidence: 99%

The sigma receptor ligand (+)−pentazocine prevents apoptotic retinal ganglion cell death induced in vitro by homocysteine and glutamate

Martin

Ola

Agarwal

et al. 2004

Molecular Brain Research

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“…Sigma receptors consist of several subtypes that are distinguishable by biochemical and pharmacological means [24]. Among these, the type 1 sigma receptor (sigma receptor 1) is the best characterized.…”

Section: Introductionmentioning

confidence: 99%

“…The cDNA encoding sigma receptor 1 was cloned originally from guinea pig liver by Hanner and colleagues [12] and more recently from human, mouse and rat [11,15,23,31,32] in our laboratory. The sigma receptor 1 cDNA predicts a protein of 223 amino acids with a single putative transmembrane domain [11,12,15,23,24,31,32]. Sigma receptor 1 is believed to mediate the immunosuppressant, antipsychotic and neuroprotective effects elicited by sigma ligands such as haloperidol, ditolylguanidine and pentazocine [10,35].…”

Section: Introductionmentioning

confidence: 99%

Expression pattern of sigma receptor 1 mRNA and protein in mammalian retina

Ola

Moore

El-Sherbeny

et al. 2001

Molecular Brain Research

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SummarySigma receptors are nonopiate and nonphencyclidine binding sites that are thought to be neuroprotective due to modulation of NMDA receptors. Sigma receptor 1 expression has been demonstrated in numerous tissues including brain. Recently, studies using binding assays have demonstrated sigma receptor 1 in neural retina, however these studies did not demonstrate in which retinal cell type(s) sigma receptor 1 was present nor did they establish unequivocally the molecular identity of the receptor. The present study was designed to address these issues. RT-PCR analysis amplified sigma receptor 1 in neural retina, RPE/choroid complex, and lens isolated from mice. A similar RT-PCR product was amplified also in three cultured cell lines, rat Müller cells, rat ganglion cells and human ARPE-19 cells. In situ hybridization analysis revealed abundant sigma receptor 1 expression in ganglion cells, cells of the inner nuclear layer, inner segments of photoreceptor cells and retinal pigment epithelial (RPE) cells. Immunohistochemical studies detected the sigma receptor 1 protein in retinal ganglion, photoreceptor, RPE cells and surrounding the soma of cells in the inner nuclear layer. These data provide the first cellular localization of sigma receptor 1 in neural retina and establish the molecular identity of sigma receptor 1 in retinal cells. The demonstration that sigma receptor 1 is present in ganglion cells is particularly noteworthy given the well-documented susceptibility of these cells to glutamate toxicity. Our findings suggest that retinal ganglion cells may be amenable to the neuroprotective effects of sigma ligands under conditions of neurotoxicity such as occurs in diabetes.

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“…Although a binding sites were originally thought to be a single entity, the current consensus is that two subtypes exist, rI and a2 (Bowen & Hellewell, 1988;Hellewell & Bowen, 1990;Knight et al, 1991a,b;Rothman et al, 1991;Quirion et al, 1992). Indeed, sophisticated computer assisted models of self and cross-displacement a ligand binding experiments have identified up to four binding sites (R-R4) for a ligands (Zhou & Musacchio, 1991;Klein & Musacchio, 1992).…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, 3PPP selectively binds to a binding sites (Weber et al, 1986). Subsequent investigations of the binding profiles of these ligands have led investigators to suggest that there are two a sites; al and a2 (Hellewell & Bowen, 1990;Quirion et al, 1992). Other groups have sug-gested that as many as four binding sites (R1 -R4) are identifiable (Zhou & Musacchio, 1991).…”

Section: Introductionmentioning

confidence: 99%

Multiple σ binding sites in guinea‐pig and rat brain membranes: G‐protein interactions

Connick¹,

Hanlon²,

Roberts³

et al. 1992

British J Pharmacology

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1 Evidence is accumulating for multiple sigma (a) sites in the mammalian CNS. 2 We have addressed this problem and have examined a site -G-protein coupling in guinea-pig and rat brain membranes. 3 Ditolylorthoguanidine (DTG), (+ )-3-(3-hydroxyphenyl)-N-l-(propyl)piperidine (3PPP) and dextromethorphan displaced [3H]-DTG (3.4 nM) with low Hill slopes of 0.5, 0.6 and 0.6, respectively in guinea-pig brain membranes. 7 The heterogeneity of a sites appears to be less in rat than in guinea-pig brain membranes.

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A proposal for the classification of sigma binding sites

Cited by 723 publications

References 23 publications

The sigma receptor ligand (+)−pentazocine prevents apoptotic retinal ganglion cell death induced in vitro by homocysteine and glutamate

The sigma receptor ligand (+)−pentazocine prevents apoptotic retinal ganglion cell death induced in vitro by homocysteine and glutamate

Expression pattern of sigma receptor 1 mRNA and protein in mammalian retina

Multiple σ binding sites in guinea‐pig and rat brain membranes: G‐protein interactions

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