Toward a unified model of vertebrate rod phototransduction

Abstract

Recently, we introduced a phototransduction model that was able to account for the reproducibility of vertebrate rod single-photon responses (SPRs) (Hamer et al., 2003). The model was able to reproduce SPR statistics by means of stochastic activation and inactivation of rhodopsin (R*), transducin (G α ), and phosphodiesterase (PDE). The features needed to capture the SPR statistics were (1) multiple steps of R* inactivation by means of multiple phosphorylations (followed by arrestin capping) and (2) phosphorylation dependence of the affinity between R* and the three molecules competing to bind with R* (G α , arrestin, and rhodopsin kinase). The model was also able to account for several other rod response features in the dim-flash regime, including SPRs obtained from rods in which various elements of the cascade have been genetically disabled or disrupted. However, the model was not tested under high light-level conditions. We sought to evaluate the extent to which the multiple phosphorylation model could simultaneously account for single-photon response behavior, as well as responses to high light levels causing complete response saturation and/or significant light adaptation (LA). To date no single model, with one set of parameters, has been able to do this. Dim-flash responses and statistics were simulated using a hybrid stochastic/ deterministic model and Monte-Carlo methods as in Hamer et al. (2003). A dark-adapted flash series, and stimulus paradigms from the literature eliciting various degrees of light adaptation (LA), were simulated using a full differential equation version of the model that included the addition of Ca 2+ -feedback onto rhodopsin kinase via recoverin. With this model, using a single set of parameters, we attempted to account for (1) SPR waveforms and statistics (as in Hamer et al., 2003); (2) a full darkadapted flash-response series, from dim flash to saturating, bright flash levels, from a toad rod; (3) steady-state LA responses, including LA circulating current (as in Koutalos et al., 1995) and LA flash sensitivity measured in rods from four species; (4) step responses from newt rods (Forti et al., 1989) over a large dynamic range; (5) dynamic LA responses, such as the step-flash paradigm of Fain et al. (1989), and the two-flash paradigm of Murnick and Lamb (1996); and (6) the salient response features from four knockout rod preparations. The model was able to meet this stringent test, accounting for almost all the salient qualitative, and many quantitative features, of the responses across this broad array of stimulus conditions, including SPR reproducibility. The model promises to be useful in testing hypotheses regarding both normal and abnormal photoreceptor function, and is a good starting point for development of a full-range model of cone phototransduction. Informative limitations of the model are also discussed.

Detection of single photons by toad and mouse rods

“…Previous models used Markov chains to account for the stochastic nature of the biochemistry (14,15) or partial differential equations to capture the complex OS geometry (16)(17)(18)(19), but here we unify these approaches into a single model. We further derive expressions for the dark noise power spectrum, which we use to estimate the values of key parameters from the analysis of dark current recordings in WT and GCAPs −/− knockout mice.…”

Regulation of Arrestin Binding by Rhodopsin Phosphorylation Level

“…An additional issue depending on this answer in the visual system is the mechanism ensuring a remarkable reproducibility of single photon response in rods. One of the explanations of this reproducibility is based on the assumption that rhodopsin is deactivated through a large number of steps (52), the great majority of which is believed to be sequential phosphorylation by rhodopsin kinase (20,33,53,54), whereas in other models multiplicity of inactivation steps is not required (55). 4 Direct binding studies with numerous reconstituted fractions containing different phosphorhodopsin species suggest that as soon as light-activated rhodopsin has two to three phosphates, arrestin can bind it with high affinity (Fig.…”

Regression of early diabetic macular oedema is associated with prevention of dark adaptation

“…The calculated light intensity at the retina was 2 scotopic Trolands, which would cause a considerable reduction in the rod dark current. 24 The device was driven by a rechargeable battery (Panasonic UL23300, Panasonic Corporation, Osaka, Japan) connected to a charge-pump chip (Max 1573, Maxim Integrated Products, Inc. Sunnyvale, CA, USA). The battery was recharged each morning.…”

“…There is Fast Track Paper Fast Track Paper considerable evidence to support this view. [13][14][15][16][17][18] These and other observations have led to a different proposal about the pathophysiology of DR. 19,[20][21][22] The oxygen demand of rods, in the outer retina, is much increased in darkness 6,7,13,[23][24][25] and this in turn causes a reduction in inner retinal oxygen tension. 11,25 It has been suggested that the increasing inner retinal hypoxia in diabetes causes the upregulation of cytokines, most importantly VEGF, to a degree that produces damage to small retinal vessels, thus reducing local capillary blood flow and increasing hypoxia in a vicious circle.…”

“…11,25 It has been suggested that the increasing inner retinal hypoxia in diabetes causes the upregulation of cytokines, most importantly VEGF, to a degree that produces damage to small retinal vessels, thus reducing local capillary blood flow and increasing hypoxia in a vicious circle. This hypothesis predicts that prevention of dark adaptation should reduce the rate of progression of DMO [22][23][24] because outer retinal hypoxia increases considerably in dark adaptation. 6 A phase I clinical trial involving 12 patients with mild non-proliferative DR showed that trans-eyelid illumination of the retina during sleep was acceptable by patients, had no reported ill effects, and also improved DR and visual function.…”