Induction of the Unfolded-Protein Response by Constitutive G-protein Signaling in Rod Photoreceptor Cells [Signal Transduction]

September 2nd, 2014 by Wang, T., Chen, J.

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, while 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 knockout 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 knockout 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 UPR induction. Taken together, these observations provide novel mechanistic insights into the cell death pathway caused by constitutive phototransduction and identify the UPR as a potential target for therapeutic intervention.