Sigma Receptors: Their Role in Disease and as Therapeutic Targets

Timur A. Mavlyutov, Lian-Wang Guo

Sylvia B. Smith, Tsung-Ping Su

This review discusses recent advances towards understanding the sigma-1 receptor (S1R) as an endogenous neuro-protective mechanism in the retina , a favorable experimental model system. The exquisite architecture of the mammalian retina features layered and intricately wired neurons supported by non-neuronal cells. Ganglion neurons, photoreceptors , as well as the retinal pigment epithelium, are susceptible to degeneration that leads to major retinal diseases such as glaucoma , diabetic retinopathy , and age-related macular degeneration (AMD), and ultimately, blindness. The S1R protein is found essentially in every retinal cell type, with high abundance in the ganglion cell layer. Ultrastructural studies of photoreceptors, bipolar cells, and ganglion cells show a predominant localization of S1R in the nuclear envelope. A protective role of S1R for ganglion and photoreceptor cells is supported by in vitro and in vivo experiments. Most recently, studies suggest that S1R may also protect retinal neurons via its activities in Müller glia and microglia. The S1R functions in the retina may be attributed to a reduction of excitotoxicity, oxidative stress , ER stress response, or inflammation. S1R knockout mice are being used to delineate the S1R-specific effects. In summary, while significant progress has been made towards the objective of establishing a S1R-targeted paradigm for retinal neuro-protection , critical questions remain. In particular, context-dependent effects and potential side effects of interventions targeting S1R need to be studied in more diverse and more clinically relevant animal models.