Benzodiazepine diazepam regulates cell surface β1-adrenergic receptor density in human monocytes

Downregulation of cell surface β-adrenergic receptors (β-AR) is an important adaptive response that prevents deleterious effects of receptor overstimulation. Various factors including reactive oxygen species cause β-AR downregulation. In this study, we evaluated the effects of ligands of the periphe...

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Published in:European journal of pharmacology 2023-06, Vol.948, p.175700-175700, Article 175700
Main Authors: Matarrese, Paola, Maccari, Sonia, Gambardella, Lucrezia, Vona, Rosa, Barbagallo, Federica, Vezzi, Vanessa, Stati, Tonino, Grò, Maria Cristina, Giovannetti, Antonello, Catalano, Liviana, Molinari, Paola, Marano, Giuseppe, Ambrosio, Caterina
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Benzodiazepines
Catecholamines
Gender
Monocytes
β1-adrenergic receptor
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container_title European journal of pharmacology
container_volume 948
creator Matarrese, Paola
Maccari, Sonia
Gambardella, Lucrezia
Vona, Rosa
Barbagallo, Federica
Vezzi, Vanessa
Stati, Tonino
Grò, Maria Cristina
Giovannetti, Antonello
Catalano, Liviana
Molinari, Paola
Marano, Giuseppe
Ambrosio, Caterina
description Downregulation of cell surface β-adrenergic receptors (β-AR) is an important adaptive response that prevents deleterious effects of receptor overstimulation. Various factors including reactive oxygen species cause β-AR downregulation. In this study, we evaluated the effects of ligands of the peripheral benzodiazepine receptor (PBR), a key protein in regulating oxidative stress, on surface density of endogenous β1-and β2-ARs in highly differentiated cells such as human monocytes, which express both β-AR subtypes. β-AR expression in human monocytes was evaluated by flow cytometry, qPCR and western blotting. Monocyte treatment with β-AR agonist isoproterenol did not change surface β1-AR density while downregulating surface β2-AR density. This effect was antagonized by the β-blocker propranolol. An opposite response was observed with benzodiazepine diazepam that led to a time-dependent reduction in β1-AR density. In particular, while no significant downregulation was observed after 3 h of treatment, only 63% of β1-ARs were still present on the cell surface after 48 h of treatment with diazepam at 1 μM. Treatment with the PBR antagonist PK11195, but not with propranolol, antagonized the effects of diazepam. No change in β1-AR-mRNA or protein levels was observed at any time after diazepam treatment. We also found that diazepam did not affect Gs-protein or β-arrestin-2 recruitment for both β-ARs in engineered fibroblasts, further suggesting that diazepam activity on β1-AR density is mediated by PBR. Finally, no sex-related differences were found. Collectively, these results indicate that monocyte β1-ARs are resistant to catecholamine-mediated downregulation and suggest that PBR plays an important role in regulating β1-AR density.
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Treatment with the PBR antagonist PK11195, but not with propranolol, antagonized the effects of diazepam. No change in β1-AR-mRNA or protein levels was observed at any time after diazepam treatment. We also found that diazepam did not affect Gs-protein or β-arrestin-2 recruitment for both β-ARs in engineered fibroblasts, further suggesting that diazepam activity on β1-AR density is mediated by PBR. Finally, no sex-related differences were found. 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subjects Benzodiazepines
Catecholamines
Gender
Monocytes
β1-adrenergic receptor
title Benzodiazepine diazepam regulates cell surface β1-adrenergic receptor density in human monocytes
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