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Towards a Unified Model of Vertebrate Rod Phototransduction, From Single–Photon to Highly Saturating Responses

¹ Retinal Computational Modeling, Smith–Kettlewell Eye Res Inst, San Francisco, CA
² Dept. of Biol. & Courant Inst. of Mathematical Sciences, NYU, New York, NY
³ Dept. of Physiology, Univ. of Cambridge, Cambridge, United Kingdom
⁴ John Curtin School of Medical Res., Australian National Univ., Canberra, Australia

Commercial Relationships: R.D. Hamer, None; S.C. Nicholas, None; D. Tranchina, None; J.L.P. Jarvinen, None; T.D. Lamb, None.

Grant Identification: EY11513–06

Abstract

Purpose: Recently, we introduced a phototransduction model that was able to resolve a 25–year old problem in photoreceptor physiology, i.e., the molecular basis of single–photon response (SPR) reproducibility (Hamer et al., J Gen Physiol 122: 419, 2003). The model included a detailed implementation of stochastic "front–end" reactions (i.e., activation and inactivation of R, G–protein and PDE), including multiple phosphorylation shutoff of R*. We applied new rigorous tests of the model by exploring its ability to account for rod response properties over a large dynamic range of light levels, and under a broad set of experimental manipulations. To date, no single model has been able to do this. Methods: 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 (up to highly saturating flashes), and stimulus paradigms eliciting various degrees of light adaptation (LA), were simulated using a full differential equation version of the model that included the addition of Ca⁺⁺–feedback onto rhodopsin kinase (RK) via recoverin (Rec). Results: The unified model: (1) Reproduced dim–flash response waveforms and statistics, including the empirical SPR reproducibility. (2) Generated a realistic DA flash response series with a saturation period (T_sat) that increased with intensity as in the empirical data. (3) Reproduced the reduction in T_sat observed when a saturating flash is preceded either by a light–adapting step (Fain et al., J Physiol 416:215, 1989) or a saturating flash (Murnick & Lamb, J Physiol 495:1, 1996). (4) Generated 2 log units of Weber’s Law flash desensitization. (5) Reproduced the salient qualitative features of rod responses from 5 genetic manipulations disabling either "front–end" recovery mechanisms or Ca⁺⁺–feedback onto cyclase.Conclusions: The unified model is able to reproduce the salient features of rod responses over a 5–log unit intensity range, including characteristics of dim–flash responses that have, historically, been difficult to account for. Nevertheless, the model does not fully account for some quantitative details of the data that will provide important clues about phototransduction.

Keywords: retina: distal (photoreceptors, horizontal cells, bipolar cells) • phosphorylation • computational modeling

© 2004, The Association for Research in Vision and Ophthalmology, Inc., all rights reserved. For permission to reproduce any part of this abstract, contact the ARVO Office at arvo{at}arvo.org.