The sigma-2 receptor agonist PB28 inhibits calcium release from the endoplasmic reticulum of SK-N-SH neuroblastoma cells

Cassano, Giuseppe; Gasparre, Giuseppe; Contino, Marialessandra; Niso, Mauro; Berardi, Francesco; Perrone, Roberto; Colabufo, Nicola Antonio

doi:10.1016/j.ceca.2006.03.004

Cited by 27 publications

(27 citation statements)

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“…Although 4 and 18 do not display s selectivity, results obtained through experiments in the cell lines selected should allow retrieval of compound effects on each s subtype: SK-N-SH cells express both s receptors, with s 1 subtype in a low affinity state; MCF-7s 1 cells overexpress s 1 receptors; MCF-7wt cells overexpress s 2 receptors. [35,36] Compound 4, as previously shown with carbachol in SK-N-SH cells, [37] inhibited bradykinin-triggered Ca 2 + response in all of the cell lines studied, whereas it did not exert any effect in LoVo colon adenocarcinoma cells in which none of the s subtypes were detected through Scatchard analysis. [35,36] Compound 4, as previously shown with carbachol in SK-N-SH cells, [37] inhibited bradykinin-triggered Ca 2 + response in all of the cell lines studied, whereas it did not exert any effect in LoVo colon adenocarcinoma cells in which none of the s subtypes were detected through Scatchard analysis.…”

Section: Chemistrysupporting

confidence: 61%

“…As previously reported, the selective s 1 agonist (+)-pentazocine increased bradykinin-induced Ca 2 + mobilization in SK-N-SH and MCF-7s 1 cells, whereas no effect was exerted in MCF-7wt cells where the s 1 density is too low (Figure 3 A). [35,36] Compound 4, as previously shown with carbachol in SK-N-SH cells, [37] inhibited bradykinin-triggered Ca 2 + response in all of the cell lines studied, whereas it did not exert any effect in LoVo colon adenocarcinoma cells in which none of the s subtypes were detected through Scatchard analysis. [36] These results support the idea that effects exerted by compound 4 in bradykinin-triggered Ca 2 + response are s-mediated and suggest that agonist activity at s 2 (from SK-N-SH and MCF-7wt) and antagonist activity at s 1 (from MCF-7s 1 ) decrease such response.…”

Section: Functional Assays: Antiproliferative Activity In Human Neurosupporting

confidence: 61%

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2‐Aminopyridine Derivatives as Potential σ₂ Receptor Antagonists

et al. 2012

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σ(2) Receptor research is receiving increasing interest with regard to the potential of σ(2) proteins as targets for tumor therapy and diagnosis. Nevertheless, knowledge about the σ(2) receptor is far from conclusive. The paucity and modest affinity of known σ(2) antagonists represent one of the limitations to σ(2) receptor research. Previous studies of the high-affinity σ(2) agonist 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperazine 4 (PB28) suggested that a decrease in lipophilicity might lead to σ(2) ligands devoid of antiproliferative activity (potential σ(2) antagonists). With the aim of producing σ(2) receptor antagonists, we replaced the tetralin nucleus of compound 4 with a 2-aminopyridine moiety. A series of compounds with high affinity for both σ subtypes and with no antiproliferative activity in various cells (mouse HT-22, human SK-N-SH, MCF-7wt, and MCF-7σ(1)) were obtained. The effect on Ca(2+) mobilization was investigated for high-affinity compounds 18 and 4, which showed opposite effects. All of the data support the new 2-aminopyridines as high-affinity σ ligands with σ(2) antagonist and σ(1) agonist activity, and, despite the lack of significant σ(2) versus σ(1) selectivity, these novel compounds may be better tools for σ receptor research than the known low-affinity σ(2) antagonists.

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Section: Chemistrysupporting

confidence: 61%

Section: Functional Assays: Antiproliferative Activity In Human Neurosupporting

confidence: 61%

2‐Aminopyridine Derivatives as Potential σ₂ Receptor Antagonists

et al. 2012

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“…Prolonged exposure of cells to sigma‐2 ligands resulted in a latent and sustained release of [Ca 2+ ] i that may signal apoptosis or related pharmacological effects. Similar results were observed with F281, a sigma‐2 agonist, in SK‐N‐SH cells, but not with PB28, a potent nonselective sigma ligand . Thus more study in the modulation of calcium ion is required to clarify this effect.…”

Section: The Pharmacology Of Sigma‐2 Receptorsupporting

confidence: 62%

“…However, some results have indicated that sigma‐2 receptor ligands activate caspase‐3, decrease the expression of p70S6K and 4EBP1 (both are downstream effectors of mTOR pathway signaling), suppress the expression of cyclin D1, and induce PARP‐1 (poly [ADP‐ribose] polymerase 1) cleavage and DNA fragmentation . Whereas some other sigma‐2 ligands were found to induce oxidative stress, mobilize intracellular calcium ion, mediate potassium channel . A more recent study conducted by Iniguez and co‐workers indicated that sigma‐2 receptor agonists significantly inhibited the induction of IL‐2 (where IL is interleukin), TNF‐α (where TNF is tumor necrosis factor), COX‐2 (where COX is cyclooxygenase), and NF‐κB (where NF is nuclear factor) in T lymphocytes .…”

Section: Sigma‐2 Receptor Signaling Pathwaysmentioning

confidence: 99%

Sigma‐2 Receptor Ligands and Their Perspectives in Cancer Diagnosis and Therapy

Huang

Zhang

et al. 2013

Medicinal Research Reviews

101

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The sigma-2 receptor is highly expressed in various rapidly proliferating cancer cells and regarded as a cancer cell biomarker. Selective sigma-2 ligands have been shown to specifically label the tumor sites, induce cancer cells to undergo apoptosis, and inhibit tumor growth. Sigma-2 ligands are potentially useful as cancer diagnostics, anticancer therapeutics, or adjuvant anticancer treatment agents. However, both the cloning of this receptor and the identification of its endogenous ligand have not been successful, and the lack of structural information has severely hindered the understanding of its physiological roles, its signaling pathways, and the development of more selective sigma-2 ligands. Recent data have implicated that sigma-2 binding sites are within the lipid rafts and that PGRMC1 (progesterone receptor membrane component 1) complex and sigma-2 receptor may be coupled with EGFR (epidermal growth factor receptor), mTOR (mammalian target of rapamycin), caspases, and ion channels. Due to its promising applications in cancer management, there are rapidly increasing research efforts that are being directed into this field. This review article updates the current understanding of sigma-2 receptor and its potential physiological roles, applications, interaction with other effectors, with special focuses on the development of sigma-2 ligands, their chemical structures, pharmacological profiles, applications in imaging and anticancer therapy.

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“…The activation of receptors has been shown previously to directly affect Ca 2ϩ release from intracellular stores (Cassano et al, 2006). Thus, experiments were conducted to resolve whether receptor activation reduces acid-induced increases in [Ca 2ϩ ] i , in part via the inhibition of calciuminduced calcium release from the endoplasmic reticulum, triggered by Ca 2ϩ influx through the plasma membrane.…”

Section: Resultsmentioning

confidence: 99%

σ-1 Receptor Modulation of Acid-Sensing Ion Channel a (ASIC1a) and ASIC1a-Induced Ca²⁺ Influx in Rat Cortical Neurons

Herrera

Katnik²,

Rodriguez³

et al. 2008

J Pharmacol Exp Ther

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Acid-sensing ion channels (ASICs) are proton-gated cation channels found in peripheral and central nervous system neurons. The ASIC1a subtype, which has high Ca 2ϩ permeability, is activated by ischemia-induced acidosis and contributes to the neuronal loss that accompanies ischemic stroke. Our laboratory has shown that activation of receptors depresses ion channel activity and [Ca 2ϩ ] i dysregulation during ischemia, which enhances neuronal survival. Whole-cell patch-clamp electrophysiology and fluorometric Ca 2ϩ imaging were used to determine whether receptors regulate the function of ASIC in cultured rat cortical neurons. Bath application of the selective ASIC1a blocker, psalmotoxin1, decreased proton-evoked [Ca 2ϩ ] i transients and peak membrane currents, suggesting the presence of homomeric ASIC1a channels. The pan-selective -1/-2 receptor agonists, 1,3-di-o-tolyl-guanidine (100 M) and opipramol (10 M), reversibly decreased acid-induced elevations in [Ca 2ϩ ] i and membrane currents. Pharmacological experiments using receptor-subtype-specific agonists demonstrated that -1, but not -2, receptors inhibit ASIC1a-induced Ca 2ϩ elevations. These results were confirmed using the irreversible receptor antagonist metaphit (50 M) and the selective -1 antagonist BD1063 (10 nM), which obtunded the inhibitory effects of the -1 agonist, carbetapentane. Activation of ASIC1a was shown to stimulate downstream Ca 2ϩ influx pathways, specifically N-methyl-D-aspartate and (Ϯ)-␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate receptors and voltage-gated Ca 2ϩ channels. These subsequent Ca 2ϩ influxes were also inhibited upon activation of -1 receptors. These findings demonstrate that -1 receptor stimulation inhibits ASIC1a-mediated membrane currents and consequent intracellular Ca 2ϩ accumulation. The ability to control ionic imbalances and Ca 2ϩ dysregulation evoked by ASIC1a activation makes receptors an attractive target for ischemic stroke therapy.Acid-sensing ion channels are a class of ligand-gated channels that are members of the degenerin/epithelial sodium channel superfamily and are expressed in both peripheral and central nervous system neurons . Thus far, four genes (ASIC1-ASIC4) and two splice variants of ASIC1 and ASIC2 (a and b) have been cloned ) that encode protein subunits that form functional proton-gated homomultimeric or heteromultimeric channels . The pH of half-maximal activation and the tissue expression patterns differ between each channel subtype.One of the most common ASIC subtypes in the central nervous system (CNS) contains the ASIC1a subunit, which can form homomultimeric or heteromultimeric channels with ASIC2a . These channels are activated by pH Յ 7 and have a pH of half-maximal activation of ϳ6.0

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The sigma-2 receptor agonist PB28 inhibits calcium release from the endoplasmic reticulum of SK-N-SH neuroblastoma cells

Cited by 27 publications

References 17 publications

2‐Aminopyridine Derivatives as Potential σ₂ Receptor Antagonists

2‐Aminopyridine Derivatives as Potential σ₂ Receptor Antagonists

Sigma‐2 Receptor Ligands and Their Perspectives in Cancer Diagnosis and Therapy

σ-1 Receptor Modulation of Acid-Sensing Ion Channel a (ASIC1a) and ASIC1a-Induced Ca²⁺ Influx in Rat Cortical Neurons

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The sigma-2 receptor agonist PB28 inhibits calcium release from the endoplasmic reticulum of SK-N-SH neuroblastoma cells

Cited by 27 publications

References 17 publications

2‐Aminopyridine Derivatives as Potential σ2 Receptor Antagonists

2‐Aminopyridine Derivatives as Potential σ2 Receptor Antagonists

Sigma‐2 Receptor Ligands and Their Perspectives in Cancer Diagnosis and Therapy

σ-1 Receptor Modulation of Acid-Sensing Ion Channel a (ASIC1a) and ASIC1a-Induced Ca2+ Influx in Rat Cortical Neurons

Contact Info

Product

Resources

About

2‐Aminopyridine Derivatives as Potential σ₂ Receptor Antagonists

2‐Aminopyridine Derivatives as Potential σ₂ Receptor Antagonists

σ-1 Receptor Modulation of Acid-Sensing Ion Channel a (ASIC1a) and ASIC1a-Induced Ca²⁺ Influx in Rat Cortical Neurons