Authors: Alice Weatherston
In a new study carried out at the Medical College of Georgia at Georgia Regents University (GA, USA) researchers have highlighted the potentially key role of a receptor, termed the sigma 1 receptor, in supporting the retina. The research, which was published recently in Free Radical Biology and Medicine, indicates a potential new treatment target for progressive retinal diseases.
The team initially discovered that the removal of sigma 1 receptors from Müller cells in the eyes of knockout mice models was sufficient to significantly increase the levels of reactive oxygen species (ROS), indicating a direct link between the receptor and the oxidative stress response which is uncontrolled in many progressive diseases.
In the retina specifically, these high levels of oxidative stress were shown to result in a breakdown in support of the neurons essential for vision and consequently the disintegration of retinal cells and vision loss.
Further examination of the sigma 1 receptor knockouts in comparison to normal mice also highlighted significantly decreased expression of the antioxidants Sod1, catalase, Nqo1, Hmox1, Gstm6, and Gpx1. Protein levels of SOD1, CAT, NQO1, and GPX1 were also significantly decreased.
The genes encoding these antioxidants contain an antioxidant response element (ARE) that under oxidative stress is activated by NRF2, a transcription factor usually found bound by KEAP1 in the cytoplasm. When needed NRF2 moves into the cell nucleus to play out it’s role as one of the most important regulators of the expression of antioxidant molecules.
Deletion of the sigma 1 receptor however altered the expected response to oxidative stress, with NRF2 expression decreasing and KEAP1 levels increasing markedly at both the gene and protein levels. NRF2–ARE binding affinity was reduced and consequently ROS levels increased.
The study is believed to provide the first evidence of the direct impact of the sigma 1 receptor on Müller cell function and more specifically on the levels of NRF2 and KEAP1. “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,” explained Sylvia Smith (Medical College of Georgia at Georgia Regents University).
The team now aim to further investigate previous findings which demonstrated the preservation of functional vision in animal models of both retinitis pigmentosa and diabetic retinopathy following administration of pentazocine, a drug which binds to and activates the sigma 1 receptor, particularly to clarify if this is a mechanism of preservation or regeneration.
“We do see some retention of function, that is clear and that I am very excited about,” concluded Smith.
Sources: Georgia Regents University press release; Wang J, Shanmugam A, Markand S et al. 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. Free Radical Biology and Medicine. 86, 25–36 (2015).