title: Modulation of cellular signaling pathways in P23H rhodopsin photoreceptors.
abstract: We previously reported activation of the unfolded protein response (UPR) in P23H rhodopsin (RHO) retinas with autosomal dominant retinitis pigmentosa (ADRP). Knowing that the UPR can trigger Ca(2+) release from the endoplasmic reticulum and regulate cellular signaling we examined the level of Ca(2+)-regulated proteins. We also looked for changes in the expression of Bcl2 family proteins, autophagy proteins and the mTOR/AKT pathways, as well as for the induction of mitochondria-associated apoptosis in the P23H RHO retina. Our data demonstrated that the elevation of calpain and caspase-12 activity was concomitantly observed with a decrease in the BCL2-XL/BAX ratio and an increase in mTor levels in the P23H-3 RHO retina suggesting a vulnerability of P23H RHO photoreceptors to apoptosis. The translocation of BAX to the mitochondria, as well as the release of cytochrome C and AIF into the cytosol supports this conclusion and indicates the involvement of mitochondria-induced apoptosis in the progression of ADRP. The level of autophagy proteins in general was found to be decreased in the P21-P30 P23H RHO retina. Injections of rapamycin, however, protected the P23H RHO rod photoreceptors from experiencing physiological decline. Despite this fact, the downregulation of mTOR did not alter the level of autophagy proteins. Our results imply that in addition to activation of the UPR during ADRP progression, photoreceptors also experience alterations in major proapoptotic pathways.
authors.affiliation: University of North Texas Health Science Center, North Texas Eye Research Institute, Department of Cell Biology and Anatomy, United States.
authors.forename: Olga S
authors.initials: OS
authors.lastname: Sizova
authors.affiliation: University of Alabama at Birmingham, Department of Visual Sciences, United States.
authors.forename: Vishal M
authors.initials: VM
authors.lastname: Shinde
authors.affiliation: University of Alabama at Birmingham, Department of Visual Sciences, United States.
authors.forename: Austin R
authors.initials: AR
authors.lastname: Lenox
authors.affiliation: University of Alabama at Birmingham, Department of Visual Sciences, United States.
authors.forename: Marina S
authors.initials: MS
authors.lastname: Gorbatyuk
mesh_terms: D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D053454:Caspase 12 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism*; D012174:Retinitis Pigmentosa / Q000378:metabolism / Q000473:pathology; D012243:Rhodopsin / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494831:Aifm1 protein, rat; D051033:Apoptosis Inducing Factor; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D012243:Rhodopsin; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D002154:Calpain; D053454:Caspase 12; D002118:Calcium
keywords: Autophagy; Calpains; Mitochondria; Rapamycin; UPR; mTOR