Not Just Signal Shutoff: The Protective Role of Arrestin-1 in Rod Cells

Abstract

The retinal rod cell is an exquisitely sensitive single-photon detector that primarily functions in dim light (e.g., moonlight). However, rod cells must routinely survive light intensities more than a billion times greater (e.g., bright daylight). One serious challenge to rod cell survival in daylight is the massive amount of all-trans-retinal that is released by Meta II, the light-activated form of the photoreceptor rhodopsin. All-trans-retinal is toxic, and its condensation products have been implicated in disease. Our recent work has developed the concept that rod arrestin (arrestin-1), which terminates Meta II signaling, has an additional role in protecting rod cells from the consequences of bright light by limiting free all-trans-retinal. In this chapter we will elaborate upon the molecular mechanisms by which arrestin-1 serves as both a single-photon response quencher as well as an instrument of rod cell survival in bright light. This discussion will take place within the framework of three distinct functional modules of vision: signal transduction, the retinoid cycle, and protein translocation.

Formation and Decay of the Arrestin·Rhodopsin Complex in Native Disc Membranes

“…The fact that only half of the receptor population is free to decay to the opsin apoprotein is consistent with our previously proposed model of asymmetric receptor dimers bound to arrestin (11). Future studies will investigate the functional roles of the different arrestin binding modes for rhodopsin (12) and GPCRs in general (57).…”

“…In the visual system, arrestin can induce the uptake of all-trans-retinal by phosphorylated opsin apoprotein (11). Based on this finding, a role for arrestin-1 as a protector of the rod cell against the toxic effects of all-transretinal has recently been proposed (12).…”

Functional trade-offs and environmental variation shaped ancient trajectories in the evolution of dim-light vision

“…Rods, in contrast, regenerate thousands of times slower than cones after bright-light exposure ( Mata et al, 2002 ). Indeed, rod exposure to bright flashes of light leads to atRAL release that can outpace clearance by visual cycle enzymes ( Sommer et al, 2014 ; Rózanowska and Sarna, 2005 ), thus leading to accumulation ( Saari et al, 1998 ; Lee et al, 2010 ) and light-induced retinopathy through various modes of cellular toxicity involving oxidative stress ( Maeda et al, 2009 ; Chen et al, 2012b ). Interestingly, recent biochemical evidence suggests MII may play a role in retinal photoprotection by complexing with arrestin after G t signaling to re-uptake and thus provide a sink for toxic atRAL after rod photobleaching ( Sommer et al, 2014 ).…”

“…Indeed, rod exposure to bright flashes of light leads to atRAL release that can outpace clearance by visual cycle enzymes ( Sommer et al, 2014 ; Rózanowska and Sarna, 2005 ), thus leading to accumulation ( Saari et al, 1998 ; Lee et al, 2010 ) and light-induced retinopathy through various modes of cellular toxicity involving oxidative stress ( Maeda et al, 2009 ; Chen et al, 2012b ). Interestingly, recent biochemical evidence suggests MII may play a role in retinal photoprotection by complexing with arrestin after G t signaling to re-uptake and thus provide a sink for toxic atRAL after rod photobleaching ( Sommer et al, 2014 ). This suggests the evolution of rhodopsin’s high conformational selectivity for toxic atRAL may be a functional specialization ( Schafer et al, 2016 ; Schafer and Farrens, 2015 ), which could in turn reflect differences in retinoid metabolism between rods vs. cones ( Wang and Kefalov, 2011 ; Tsybovsky and Palczewski, 2015 ; Imai et al, 2005 ).…”

Protein and Signaling Networks in Vertebrate Photoreceptor Cells

“…All activation steps of the excitation pathway need efficient shut-off mechanisms (Burns, 2010 ). Thus, rhodopsin is phosphorylated by rhodopsin kinase (GRK1) under control of Ca 2+ /recoverin (Senin et al, 2002b ) and competitive binding of arrestin to phospho-rhodopsin prevents further interaction of transducin with rhodopsin (Sommer et al, 2014 ). As regards the effector, the acceleration of the intrinsic GTPase activity of transducin by RGS9-1 and accessory proteins Gβ5L and R9AP leads to a sub-second deactivation of transducin (Wensel, 2008 ), which in turns dissociates from PDE6, thus restoring the low basal activity controlled by its small inhibitory γ subunits.…”