Sigma Receptors: Their Role in Disease and as Therapeutic Targets

Jing Wang, Xuezhi Cui, Penny Roon, Alan Saul, Sylvia B. Smith Ph.D., Sylvia B. Smith

Sylvia B. Smith, Tsung-Ping Su

This review article focuses on studies of Sigma 1 Receptor (Sigma1R) and retina . It provides a brief overview of the earliest pharmacological studies performed in the late 1990s that provided evidence of the presence of Sigma1R in various ocular tissues. It then describes work from a number of labs concerning the location of Sigma1R in several retinal cell types including ganglion, Müller glia , and photoreceptors . The role of Sigma1R ligands in retinal neuroprotection is emphasized. Early studies performed in vitro clearly showed that targeting Sigma1R could attenuate stress-induced retinal cell loss. These studies were followed by in vivo experiments. Data about the usefulness of targeting Sigma1R to prevent ganglion cell loss associated with diabetic retinopathy are reviewed. Mechanisms of Sigma1R-mediated retinal neuroprotection involving Müller cells , especially in modulating oxidative stress are described along with information about the retinal phenotype of mice lacking Sigma1R (Sigma1R (-/-) mice). The retina develops normally in Sigma1R (-/-) mice, but after many months there is evidence of apoptosis in the optic nerve head, decreased ganglion cell function and eventual loss of these cells. Additional studies using the Sigma1R (-/-) mice provide strong evidence that in the retina, Sigma1R plays a key role in modulating cellular stress. Recent work has shown that targeting Sigma1R may extend beyond protection of ganglion cells to include photoreceptor cell degeneration as well.