Nonredundant Role of Akt2 for Neuroprotection of Rod Photoreceptor Cells from Light-Induced Cell Death

Abstract

The Akt kinases mediate cell survival through phosphorylation and inactivation of apoptotic machinery components. Akt signaling provides a trophic signal for transformed retinal neurons in culture, but the in vivo role of Akt activity is unknown. In this study, we found that all three Akt isoforms were expressed in rod photoreceptor cells. We investigated the functional roles of Akt1 and Akt2, two of the isoforms of Akt, and their biological significance in light-induced retinal degeneration. Consistent with the hypothesis that Akt activity is important to circumvent stress-induced apoptosis, herein we report the novel finding that rod photoreceptor cells in Akt2 knock-out mice exhibited a significantly greater sensitivity to stress-induced cell death than rods in heterozygous or wild-type mice. Under similar conditions, Akt1 deletion had no effect on the retina. The presence of three Akt isoforms in the retina is suggestive of a functional redundancy; however, our studies clearly demonstrate that, under stress, Akt1 and Akt3 cannot complement the specific survival signals driven by Akt2. Furthermore, we show that Akt2 is specially activated is response to light stress. The results presented in this study provide the first direct evidence that Akt2 has a nonredundant neuroprotective role in photoreceptor survival and maintenance.

Insulin Receptor Signaling in Cones

“…One of the differences is in ATP consumption, as its consumption is significantly reduced in rods during the day, whereas it is increased in cones (33). We have previously reported that deletion of Akt2 in rods resulted in photoreceptor degeneration (34) but not in cones as we observed in this study.…”

“…In this study, deletion of individual Akt isoforms, Akt1, Akt2, and Akt3, did not show any retinal phenotype, suggesting a functional redundancy exists among Akt isoforms. Surprisingly, in rods, Akt2 deletion has both a functional and a structural phenotype, enforcing a non-redundant role of Akt2 in rod photoreceptor function (34).…”

Phosphoinositide 3-kinase signaling in the vertebrate retina

“…Because bright light stimulation can cause the death of rod and cone photoreceptor cells ( 176,177 ), activation of the PI3K/Akt pathway by relatively modest light levels may serve to prevent death of photoreceptors. Supporting this hypothesis are the data that show deletion of Akt2, one of the isoforms of Akt, results in stress-induced photoreceptor degeneration ( 135 ). Furthermore, rod-specifi c IR knockout mice have reduced PI3K and Akt recruitment to the membranes, suggesting that the IR regulates the downstream PI3K and Akt survival signal in rod photoreceptors ( 148 ).…”

“…These studies suggested that PTP1B is a novel substrate for Akt and that phosphorylation of PTP1B by Akt at Ser 50 may negatively modulate its phosphatase activity, creating a positive feedback mechanism for IR/PI3K signaling. Currently, we do not know whether such a mechanism exists in the retina; however, Akt2 knockout mice have increased susceptibility to light-induced photoreceptor degeneration ( 135 ). It is possible that failure to deactivate PTP1B by Akt2 may result in the degeneration phenotype.…”

“…PI3K-generated phosphoinositides are involved in the membrane targeting of rhodopsin as well as disc morphogenesis in mammalian photoreceptors ( 242 ). In the retina, deletion of the PI-binding proteins Akt2 ( 135 ) and IRS-2 ( 69 ) results in photoreceptor degeneration. Drosophila arrestin has a PI-binding domain that binds PI-3,4,5-P 3 and controls the movement of arrestin ( 243 ).…”