Abstract
The sigma 1 receptor (S1R) is a unique transmembrane protein that has been shown to regulate neuronal differentiation and cellular survival. It is expressed within several cell types throughout the nervous system and visceral organs, including neurons and glia within the eye. S1R ligands are therapeutic targets for diseases ranging from neurodegenerative conditions to neoplastic disorders. However, effects of S1R activation and inhibition within glia cells are not well characterized. Within the eye, the astrocytes at the optic nerve head are crucial to the health and survival of the neurons that send visual information to the brain. In this study, we used the S1R-specific agonist, (+)-pentazocine, to evaluate S1R activation within optic nerve head-derived astrocytes (ONHAs). Treatment of ONHAs with (+)-pentazocine attenuated the level and duration of stress-induced ERK phosphorylation following oxidative stress exposure and promoted survival of ONHAs. These effects were specific to S1R activation because they were not observed in ONHAs that were depleted of S1R using siRNA-mediated knockdown. Collectively, our results suggest that S1R activation suppresses ERK1/2 phosphorylation and protects ONHAs from oxidative stress-induced death.
Highlights
Sigma 1 receptor (S1R) is a small (25kDa), transmembrane protein that is highly conserved but has no known homology to existing mammalian proteins[1]
Previous work indicated that S1R is expressed within the retinal ganglion cells (RGCs) and glial cells of the optic nerve, but it has not been evaluated in optic nerve head astrocytes (ONHAs) [16]
Consistent with previous studies of oxidative stress-exposed astrocytes, we found that exposure of ONHAs to H2O2 led to increased levels of pERK1/2 at time points of 15 minutes to 24 hours following application, with peak activation occurring at the 30 minute time point (Fig 4A)[38]
Summary
Sigma 1 receptor (S1R) is a small (25kDa), transmembrane protein that is highly conserved but has no known homology to existing mammalian proteins[1]. Our recent work describes enhancement of retinal ERK1/2 phosphorylation concomitant with robust protection from excitotoxic injury within retinas of (+)-pentazocine-treated mice[20] These recent results are in contrast with findings of (+)-pentazocine-mediated decreased ERK1/2 activation within primary microglia cell cultures derived from retina[28]. The optic nerve head astrocytes (ONHAs) are the most common glial cells within the ONH They are vital to the health of the RGCs. They are vital to the health of the RGCs Evaluating their response to S1R activation and inhibition is critical to understanding ophthalmic treatment effects of S1R agonists and antagonists. Our results suggest that S1R activation protects ONHAs via a mechanism that likely involves modulation of the ERK1/2 signaling pathway
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