Sigma-1 Receptor Agonists Acting on Aquaporin-Mediated H2O2 Permeability: New Tools for Counteracting Oxidative Stress.

Giorgia Pellavio,Daniela Rossi,Umberto Laforenza,Simona Collina,Giulia Gastaldi,Pasquale Linciano,Giacomo Rossino

doi:10.3390/ijms22189790

Giorgia Pellavio, Daniela Rossi + Show 5 more

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https://doi.org/10.3390/ijms22189790

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Abstract

Sigma1 Receptor (S1R) is involved in oxidative stress, since its activation is triggered by oxidative or endoplasmic reticulum stress. Since specific aquaporins (AQP), called peroxiporins, play a relevant role in controlling H2O2 permeability and ensure reactive oxygen species wasted during oxidative stress, we studied the effect of S1R modulators on AQP-dependent water and hydrogen peroxide permeability in the presence and in the absence of oxidative stress. Applying stopped-flow light scattering and fluorescent probe methods, water and hydrogen peroxide permeability in HeLa cells have been studied. Results evidenced that S1R agonists can restore water permeability in heat-stressed cells and the co-administration with a S1R antagonist totally counteracted the ability to restore the water permeability. Moreover, compounds were able to counteract the oxidative stress of HeLa cells specifically knocked down for S1R. Taken together these results support the hypothesis that the antioxidant mechanism is mediated by both S1R and AQP-mediated H2O2 permeability. The finding that small molecules can act on both S1R and AQP-mediated H2O2 permeability opens a new direction toward the identification of innovative drugs able to regulate cell survival during oxidative stress in pathologic conditions, such as cancer and degenerative diseases.

Highlights

Hydrogen peroxide (H2 O2 ) is the most abundant and stable reactive oxygen species (ROS) in living cells [1]
Heat was used as a physiological stressor able to reduce water permeability in cells,2.asResults reported by previous works [4,20]
Once the profile of well-known Sigma1 Receptor (S1R) modulators was assessed in water permeability assays, we extended the investigation to compounds 1–3, belonging to a library of aryl aminoalkyl ketones with S1R binding affinity and antioxidant properties [45]

Summary

Introduction

Hydrogen peroxide (H2 O2 ) is the most abundant and stable reactive oxygen species (ROS) in living cells [1]. The cells dispose of H2 O2 either by intracellular antioxidant systems or by outflow through the plasma membrane. H2 O2 crosses the biological membranes through a diffusion-facilitating channel mechanism mediated by Aquaporins (AQPs) [1,3,7]. AQPs are integral membrane proteins forming channels in the biological membranes, and are mainly involved in the transport of water and small molecules (i.e., ammonia, glycerol) [8,9]. The control of peroxiporins-mediated H2 O2 permeability seems to have a great importance in regulating cell signaling and survival during oxidative stress [4,19,20,21]. The functioning of peroxiporins is critical to ensure ROS wasting and is considered an antioxidant system. Various cellular stress conditions, including heat and incubation with H2 O2 , reduce the AQP-mediated H2 O2 transport [4,19,20,21]

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