title: Induction of the unfolded protein response by constitutive G-protein signaling in rod photoreceptor cells.
abstract: Phototransduction is a G-protein signal transduction cascade that converts photon absorption to a change in current at the plasma membrane. Certain genetic mutations affecting the proteins in the phototransduction cascade cause blinding disorders in humans. Some of these mutations serve as a genetic source of "equivalent light" that activates the cascade, whereas other mutations lead to amplification of the light response. How constitutive phototransduction causes photoreceptor cell death is poorly understood. We showed that persistent G-protein signaling, which occurs in rod arrestin and rhodopsin kinase knock-out mice, caused a rapid and specific induction of the PERK pathway of the unfolded protein response. These changes were not observed in the cGMP-gated channel knock-out rods, an equivalent light condition that mimics light-stimulated channel closure. Thus transducin signaling, but not channel closure, triggers rapid cell death in light damage caused by constitutive phototransduction. Additionally, we show that in the albino light damage model cell death was not associated with increase in global protein ubiquitination or unfolded protein response induction. Taken together, these observations provide novel mechanistic insights into the cell death pathway caused by constitutive phototransduction and identify the unfolded protein response as a potential target for therapeutic intervention.
authors.affiliation: From the Program in Genetic, Molecular and Cellular Biology and the Zilkha Neurogenetic Institute, Department of Cell & Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089.
authors.forename: Tian
authors.initials: T
authors.lastname: Wang
authors.affiliation: the Zilkha Neurogenetic Institute, Department of Cell & Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089 jeannie@usc.edu.
authors.forename: Jeannie
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics; D016923:Cell Death; D002470:Cell Survival; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics; D059865:Endoplasmic Reticulum Stress; D051606:G-Protein-Coupled Receptor Kinase 1 / Q000235:genetics; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics; D019204:GTP-Binding Proteins / Q000378:metabolism*; D008027:Light; D055537:Light Signal Transduction; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism* / Q000528:radiation effects; D012243:Rhodopsin / Q000235:genetics; D015398:Signal Transduction; D015293:Transducin / Q000235:genetics; D056811:Unfolded Protein Response; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; C529481:Cngb1 protein, mouse; D054815:Cyclic Nucleotide-Gated Cation Channels; D044385:GTP-Binding Protein alpha Subunits; C488949:Gnat1 protein, mouse; D009419:Nerve Tissue Proteins; D000071557:beta-Arrestins; D012243:Rhodopsin; D051606:G-Protein-Coupled Receptor Kinase 1; C496762:Grk1 protein, mouse; D019204:GTP-Binding Proteins; D015293:Transducin
keywords: G-protein; Light Damage; Photoreceptor; Retinal Degeneration; Rhodopsin; Unfolded Protein Response (UPR)