Protective Receptor Plays Key Role in Supporting the Retina

A receptor that is already a target for treating neurodegenerative disease also appears to play a key role in supporting the retina, scientists report.

Without sigma 1 receptor, the Müller cells that support the retina can’t seem to control their own levels of destructive oxidative stress, and consequently can’t properly support the millions of specialized neurons that enable us to transform light into images, scientists report in the journal Free Radical Biology and Medicine.

Without support, well-organized layers of retinal cells begin to disintegrate and vision is lost to diseases such as retinitis pigmentosa, diabetic retinopathy and glaucoma, said Dr. Sylvia Smith, retinal cell biologist and Chairwoman of the Department of Cellular Biology and Anatomy at the Medical College of Georgia at Georgia Regents University

The surprising finding makes the sigma 1 receptor a logical treatment target for these typically progressive and blinding retinal diseases, said Smith, the study’s corresponding author. It has implications as well for other major diseases, such as cardiovascular disease and cancer as well as neurodegenerative disease, where oxidative stress plays a role.

What most surprised the scientists was that simply removing sigma 1 receptor from Müller cells significantly increased levels of reactive oxygen species, or ROS, indicating the receptor’s direct role in the oxidative stress response, Smith said. They expected it would take them giving an oxidative stressor to increase ROS levels.

So they looked further at the sigma 1 receptor knockouts compared with normal mice, and found significantly decreased expression in the knockouts of several, well-known antioxidant genes and their proteins. Further examination showed a change in the usual stress response.

These genes that make natural antioxidants contain antioxidant response element, or ARE which, in the face of oxidative stress, gets activated by NRF2, a transcription factor that usually stays in the fluid part of the cell, or cytoplasm. NRF2 is considered one of the most important regulators of the expression of antioxidant molecules. Normally the protein KEAP1 keeps it essentially inactive in the cytoplasm until needed, then it moves to the cell nucleus where it can help mount a defense. “When you have oxidative stress, you want this,” Smith said of the stress response, which works the same throughout the body.

Deleting the sigma receptor in the Müller cells altered the desired response: NRF2 expression decreased while KEAP1 expression increased. The unhealthy bottom line was that ROS levels increased as well.

The study is believed to provide the first evidence of the direct impact of the sigma 1 receptor on the levels of NRF2 and KEAP1, the researchers write.

“We think we are beginning to understand the mechanism by which sigma 1 receptor may work and it may work because of its action on releasing antioxidant genes,” Smith said.

While the ubiquitous receptor was known to help protect neurons in the brain and eye, its impact on Müller cell function was previously unknown. The significant impact the MCG scientists have now found helps explain the dramatic change they documented after using pentazocine, a narcotic already used for pain relief, in animal models of both retinitis pigmentosa and diabetic retinopathy. Pentazocine, which binds to and activates the sigma 1 receptor, seems to preserve functional vision in these disease models by enabling many of the well-stratified layers of photoreceptor cells to survive.

Next steps include clarifying whether it’s actually preservation or regeneration of the essential cell layers and how long the effect lasts. “We do see some retention of function, that is clear and that I am very excited about,” Smith said.

This is a drawing of a section of the retina.
What most surprised the scientists was that simply removing sigma 1 receptor from Müller cells significantly increased levels of reactive oxygen species, or ROS, indicating the receptor’s direct role in the oxidative stress response, Smith said. They expected it would take them giving an oxidative stressor to increase ROS levels. This image is for illustrative purposes only. Image credit: Henry Gray.

Müller cells are major support cells for the retina, helping stabilize its complex, multi-layer structure, both horizontally and vertically; eliminating debris; and supporting the function and metabolism of its neurons and blood vessels. Typically bustling Müller cells can become even more activated when there is an insult to the eye, such as increased oxidative stress, and start forming scar tissue, which hinders rather than supports vision. Problems such as diabetes, can increase ROS levels.

ROS are molecules produced through normal body function such as breathing and cells using energy. The body needs a limited amount of ROS to carry out additional functions, such as cell signaling. Problems, from eye disease to cancer, result when the body’s natural system for eliminating excess ROS can’t keep up and ROS start to do harm, such as cell destruction.

Normally humans have about 125 million night-vision enabling rods intermingled with about 6 million cones that enable us to respond to light and see color.

About this neuroscience research

Funding: The research was supported by the National Eye Institute and the James and Jean Culver Vision Discovery Institute at GRU. MCG Assistant Research Scientist Dr. Jing Wang is the study’s first author.

Source: Toni Baker – Georgia Regents University Medical College
Image Credit: The image is credited to Henry Gray and is in the public domain
Original Research: Abstract for “Sigma 1 receptor regulates the oxidative stress response in primary retinal Müller glial cells via NRF2 signaling and system xc−, the Na+-independent glutamate–cystine exchanger” by Jing Wang, Arul Shanmugam, Shanu Markand, Eric Zorrilla, Vadivel Ganapathy, and Sylvia B. Smith in Free Radical Biology and Medicine. Published online August 2015 doi:10.1016/j.freeradbiomed.2015.04.009


Abstract

Sigma 1 receptor regulates the oxidative stress response in primary retinal Müller glial cells via NRF2 signaling and system xc−, the Na+-independent glutamate–cystine exchanger

Oxidative stress figures prominently in retinal diseases, including diabetic retinopathy, and glaucoma. Ligands for σ1R, a unique transmembrane protein localized to the endoplasmic reticulum, mitochondria, and nuclear and plasma membranes, have profound retinal neuroprotective properties in vitro and in vivo. Studies to determine the mechanism of σ1R-mediated retinal neuroprotection have focused mainly on neurons. Little is known about the effects of σ1R on Müller cell function, yet these radial glial cells are essential for homeostatic support of the retina. Here we investigated whether σ1R mediates the oxidative stress response of Müller cells using wild-type (WT) and σ1R-knockout (σ1RKO) mice. We observed increased endogenous reactive oxygen species (ROS) levels in σ1RKO Müller cells compared to WT, which was accompanied by decreased expression of Sod1, catalase, Nqo1, Hmox1, Gstm6, and Gpx1. The protein levels of SOD1, CAT, NQO1, and GPX1 were also significantly decreased. The genes encoding these antioxidants contain an antioxidant response element (ARE), which under stress is activated by NRF2, a transcription factor that typically resides in the cytoplasm bound by KEAP1. In the σ1RKO Müller cells Nrf2 expression was decreased significantly at the gene (and protein) level, whereas Keap1 gene (and protein) levels were markedly increased. NRF2–ARE binding affinity was decreased markedly in σ1RKO Müller cells. We investigated system xc−, the cystine–glutamate exchanger important for synthesis of glutathione (GSH), and observed decreased function in σ1RKO Müller cells compared to WT as well as decreased GSH and GSH/GSSG ratios. This was accompanied by decreased gene and protein levels of xCT, the unique component of system xc−. We conclude that Müller glial cells lacking σ1R manifest elevated ROS, perturbation of antioxidant balance, suppression of NRF2 signaling, and impaired function of system xc−. The data suggest that the oxidative stress-mediating function of retinal Müller glial cells may be compromised in the absence of σ1R. The neuroprotective role of σ1R may be linked directly to the oxidative stress-mediating properties of supportive glial cells.

“Sigma 1 receptor regulates the oxidative stress response in primary retinal Müller glial cells via NRF2 signaling and system xc−, the Na+-independent glutamate–cystine exchanger” by Jing Wang, Arul Shanmugam, Shanu Markand, Eric Zorrilla, Vadivel Ganapathy, and Sylvia B. Smith in Free Radical Biology and Medicine. Published online August 2015 doi:10.1016/j.freeradbiomed.2015.04.009

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