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Updated: Mar 19, 2026
Imaging Ca2+ Dynamics in Cone Photoreceptor Axon Terminals of the Mouse Retina
Published on: May 6, 2015
Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited
Jing Wang1, Alan Saul2, Penny Roon3
1Department of Cellular Biology/Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA 30912;
Abstract:
Retinal degenerative diseases are major causes of untreatable blindness, and novel approaches to treatment are being sought actively. Here we explored the activation of a unique protein, sigma 1 receptor (Sig1R), in the treatment of PRC loss because of its multifaceted role in cellular survival. We used Pde6β(rd10) (rd10) mice, which harbor a mutation in the rod-specific phosphodiesterase gene Pde6β and lose rod and cone photoreceptor cells (PRC) within the first 6 wk of life, as a model for severe retinal degeneration. Systemic administration of the high-affinity Sig1R ligand (+)-pentazocine [(+)-PTZ] to rd10 mice over several weeks led to the rescue of cone function as indicated by electroretinographic recordings using natural noise stimuli and preservation of cone cells upon spectral domain optical coherence tomography and retinal histological examination. The protective effect appears to result from the activation of Sig1R, because rd10/Sig1R(-/-) mice administered (+)-PTZ exhibited no cone preservation. (+)-PTZ treatment was associated with several beneficial cellular phenomena including attenuated reactive gliosis, reduced microglial activation, and decreased oxidative stress in mutant retinas. To our knowledge, this is the first report that activation of Sig1R attenuates inherited PRC loss. The findings may have far-reaching therapeutic implications for retinal neurodegenerative diseases.
Insights
Activation of the sigma 1 receptor (Sig1R) with (+)-pentazocine protected cone photoreceptor cells in a mouse model of inherited retinal degeneration. This offers a potential new therapeutic strategy for untreatable blindness.
Area of Science:
- Neuroscience
- Ophthalmology
- Genetics
Background:
- Retinal degenerative diseases cause untreatable blindness.
- Novel therapeutic strategies are urgently needed.
- The sigma 1 receptor (Sig1R) plays a role in cellular survival.
Purpose of the Study:
- To investigate the potential of Sig1R activation for treating photoreceptor cell (PRC) loss.
- To evaluate the therapeutic efficacy of (+)-pentazocine [(+)-PTZ] in a mouse model of retinal degeneration.
Main Methods:
- Utilized Pde6β(rd10) (rd10) mice, a model for severe retinal degeneration with PRC loss.
- Administered (+)-PTZ systemically to rd10 mice.
- Assessed cone function via electroretinography and structural preservation using OCT and histology.
- Confirmed Sig1R-dependent effects by testing (+)-PTZ in rd10/Sig1R(-/-) mice.
Main Results:
- (+)-PTZ treatment rescued cone function and preserved cone cells in rd10 mice.
- The protective effect was dependent on Sig1R activation, as rd10/Sig1R(-/-) mice showed no benefit.
- (+)-PTZ treatment reduced reactive gliosis, microglial activation, and oxidative stress.
Conclusions:
- Sig1R activation by (+)-PTZ attenuates inherited photoreceptor cell loss.
- This study provides the first evidence for Sig1R activation as a treatment for inherited PRC loss.
- Findings suggest Sig1R activation may have broad therapeutic implications for retinal neurodegenerative diseases.
