Light, Ca2+, and photoreceptor death: new evidence for the equivalent-light hypothesis from arrestin knockout mice.

In this issue of Investigative Ophthalmology and Visual Science, Chen et al. show that light exposure can greatly accelerate light damage in arrestin knockout mice. Arrestin and its splice variant p44 are soluble proteins that bind to phosphorylated rhodopsin and prevent the binding of rhodopsin to the G-protein transducin. Arrestin therefore plays a key role in turning off the visual cascade, and animals without arrestin show greatly prolonged light responses. Chen et al. show that when arrestin knockout mice are placed in constant light too dim to produce degeneration in normal animals, the photoreceptors rapidly degenerate; but if animals are kept in darkness, no degeneration occurs. These results provide strong evidence that light itself, in conjunction with the slow turnoff of the photoresponse in the arrestin knockout animals, is directly responsible for the degeneration of the photoreceptors. Arrestin knockout mice also show some evidence of degeneration in cyclic (12-hour light–12-hour dark) light, but the loss of photoreceptors is very slow. This slow rate of degeneration is broadly consistent with the progression of Oguchi disease in humans, a form of stationary night blindness that in some patients is apparently produced by mutations in the arrestin gene. The results of Chen et al. raise the important question of how light exposure produces photoreceptor death. Although it has long been known that continuous exposure to light can produce degeneration, the significance of this observation has been unclear, first because degeneration is much more pronounced in albino animals than in pigmented animals, and second because there is no agreement about how light damage occurs. In many previous reports, the intensity of the continuous light used to produce degeneration was high enough to produce a nonspecific, toxic effect of illumination. The experiments of Chen et al. show that in arrestin knockout animals, light can produce degeneration even in pigmented animals at intensities that have no effect on normal pigmented mice. It is therefore very unlikely in these experiments that light had some nonspecific effect such as photodynamic damage. A more probable explanation is that in normal pigmented animals, the light was not bright enough to saturate the photoresponse, but in arrestin knockout animals, the pronounced decay of the single-photon response produced a more strongly maintained suppression of the photocurrent. As Chen et al. concluded, the degeneration in arrestin knockout animals is probably caused by constitutive activation of the visual cascade. We have previously proposed that degeneration in continuous light and in certain forms of retinitis pigmentosa may be caused by constitutive activation of the photoreceptor. This equivalent-light hypothesis of retinal degeneration has received recent support, not only from the findings of Chen et al., but also from similar observations in rhodopsin kinase (RK) knockout animals and from the discovery of new forms of photoreceptor dystrophies for which constitutive activation of the visual cascade is the most likely explanation for degeneration. These include mutations of the rod a subunit of the cyclic guanosine monophosphate (cGMP)–gated channel and of the retinal guanylyl cyclase (RetGC-1). Mutations of the channel leave the photoreceptor outer segment with almost no resting influx of Na or Ca, much as if the receptor were constantly exposed to a very bright light (Fig. 1). Similarly, mutations of the cyclase prevent the synthesis of cGMP, resulting in a very low resting cGMP concentration and closure of the cGMPgated channels. Thus, both these mutations lead to a situation in which the rod is continuously hyperpolarized in the dark, just as it would be during saturating continuous light. This equivalent-light signal produced in the photoreceptors is apparently also signaled to other retinal cells. The best evidence for this comes from recent work in the chicken retina, where the pigment granules of the retinal pigment epithelium take a very different position when the animal is in the light or the dark. In chick rd animals in which one form of guanylyl cyclase (RetGC-1) is absent, the pigment granules remain in the “light” configuration, even when the animals are kept in darkness. The photoreceptors in these animals are apparently sending a signal to the pigment epithelial cells that is equivalent to the one that occurs in light.