Date of Award

3-12-2008

Degree Type

Restricted Access Dissertation

Degree Name

Doctor of Philosophy

Department

Graduate School of Biomedical Sciences

First Advisor

Thomas Yorio

Second Advisor

Meharvan Singh

Third Advisor

Tina Machu

Abstract

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.

Comments

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 W 4 T251S 2008

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