Sigma-1 Receptor Signaling in the Eye

SIGMA-1 Receptor Signaling in the Eye Kissaou T. Tchedre, Department of Biomedical Sciences, University of North Texas Health Science Center Fort Worth, TX 76107. SUMMARY The sigma-1 receptor is a discovered transmembrane protein that mediates the regulation of ion channels. Sigma-1 receptor ligands have exhibited a wide variety of actions in the central nervous system including attenuation of the neuronal death associated with glutamate excitotoxicity both in vitro and in vivo. Although the sigma-1 receptor was cloned almost a decade ago, the molecular mechanism of the neuroprotective effect remains to be elucidated. In the current proposal it was hypothesized that activation of sigma-1 receptors promotes retinal ganglion cells survival by decreased calcium signaling pathways and factors linked to cell death. We showed by the ratiometric calcium imaging and patch clamp techniques that sigma-1 receptor activation could inhibit both calcium influx and intracellular calcium mobilization. The results showed that sigma-1 receptor overexpressing RGC-5 cells also had a lower glutamate-induced intracellular calcium mobilization compared to non-overexpressing RGC-5 cells. The survival assay data showed that the sigma-1 receptor agonist, (+)-SKF10047 protected RGC-5 cells showed a significant resistance to glutamate-induced apoptosis compared to the control RGC-5 cells. The sigma-1 receptor neuroprotective mechanism also included the down regulation of Bax, and caveolin-1 protein expression levels and inhibited caspase-3 activation. We also demonstrated for the first time using a co-immunoprecipitation technique, the association between L-type calcium channels and sigma-1 receptors. Thus sigma-1 receptor ligands may indirectly influence the voltage-gated calcium channels by interacting with the sigma-1 receptor associated voltage-gated calcium channel complex. In conclusion, activation of sigma-1 receptors can regulate calcium homeostasis and signaling in retinal ganglion cells. Activation of sigma-1 receptors regulate intracellular calcium levels and pro-apoptotic gene expression to promote retinal ganglion cell survival. Sigma-1 receptor ligands may be neuroprotective and targets for potential glaucoma therapeutics.