Sigma-1 Receptor Signaling in the Eye

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dc.contributor.advisorYorio, Thomas
dc.contributor.committeeMemberSingh, Meharvan
dc.contributor.committeeMemberMachu, Tina
dc.creatorTchedre, Kissaou T.
dc.date.accessioned2019-08-22T21:10:55Z
dc.date.available2019-08-22T21:10:55Z
dc.date.issued2008-03-12
dc.date.submitted2013-11-05T06:54:04-08:00
dc.description.abstractSIGMA-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.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/20.500.12503/29134
dc.language.isoen
dc.provenance.legacyDownloads0
dc.subjectCell Anatomy
dc.subjectCell and Developmental Biology
dc.subjectCell Biology
dc.subjectCells
dc.subjectCellular and Molecular Physiology
dc.subjectLife Sciences
dc.subjectMedical Cell Biology
dc.subjectMedicine and Health Sciences
dc.subjectOphthalmology
dc.subjectOptometry
dc.subjectOther Cell and Developmental Biology
dc.subjectSense Organs
dc.subjectVision Science
dc.subjectSIGMA-1 receptor signaling
dc.subjecteye
dc.subjecttransmembrane protein
dc.subjection channel
dc.subjectregulation
dc.subjectneuroprotection
dc.subjectcell death
dc.subjectretinal ganglion cells
dc.subjectintracellular calcium levels
dc.subjectapoptosis
dc.subjectglaucoma therapeutics
dc.titleSigma-1 Receptor Signaling in the Eye
dc.typeDissertation
dc.type.materialtext
thesis.degree.departmentGraduate School of Biomedical Sciences
thesis.degree.grantorUniversity of North Texas Health Science Center at Fort Worth
thesis.degree.nameDoctor of Philosophy

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