Sigma 1 receptor: A novel therapeutic target in retinal disease

Retinal degenerative diseases are major causes of untreatable blindness worldwide and efficacious treatments for these diseases are sorely needed. A novel target for treatment of retinal disease is the transmembrane protein Sigma 1 Receptor (Sig1R). This enigmatic protein is an evolutionary isolate with no known homology to any other protein. Sig1R was originally thought to be an opioid receptor. That notion has been dispelled and more recent pharmacological and molecular studies suggest that it is a pluripotent modulator with a number of biological functions, many of which are relevant to retinal disease. This review provides an overview of the discovery of Sig1R and early pharmacologic studies that led to the cloning of the Sig1R gene and eventual elucidation of its crystal structure. Studies of Sig1R in the eye were not reported until the late 1990s, but since that time there has been increasing interest in the potential role of Sig1R as a target for retinal disease. Studies have focused on elucidating the mechanism(s) of Sig1R function in retina including calcium regulation, modulation of oxidative stress, ion channel regulation and molecular chaperone activity. Mechanistic studies have been performed in isolated retinal cells, such as Müller glial cells, microglial cells, optic nerve head astrocytes and retinal ganglion cells as well as in the intact retina. Several compelling studies have provided evidence of powerful in vivo neuroprotective effects against ganglion cell loss as well as photoreceptor cell loss. Also described are studies that have examined retinal structure/function in various models of retinal disease in which Sig1R is absent and reveal that these phenotypes are accelerated compared to retinas of animals that express Sig1R. The collective evidence from analysis of studies over the past 20 years is that Sig1R plays a key role in modulating retinal cellular stress and that it holds great promise as a target in retinal neurodegenerative disease.