A quantitative account of mammalian rod phototransduction with PDE6 dimeric activation: responses to bright flashes.

Trevor D Lamb,Timothy W Kraft

doi:10.1098/rsob.190241

Trevor D Lamb, Timothy W Kraft

Open Access

https://doi.org/10.1098/rsob.190241

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Abstract

We develop an improved quantitative model of mammalian rod phototransduction, and we apply it to the prediction of responses to bright flashes of light. We take account of the recently characterized dimeric nature of PDE6 activation, where the configuration of primary importance has two transducin molecules bound. We simulate the stochastic nature of the activation and shut-off reactions to generate the predicted kinetics of the active molecular species on the disc membrane surfaces, and then we integrate the differential equations for the downstream cytoplasmic reactions to obtain the predicted electrical responses. The simulated responses recover the qualitative form of bright-flash response families recorded from mammalian rod photoreceptors. Furthermore, they provide an accurate description of the relationship between the time spent in saturation and flash intensity, predicting the transition between first and second ‘dominant time constants’ to occur at an intensity around 5000 isomerizations per flash, when the rate of transducin activation is taken to be 1250 transducins s−1 per activated rhodopsin. This rate is consistent with estimates from light-scattering experiments, but is around fourfold higher than has typically been assumed in other studies. We conclude that our model and parameters provide a compelling description of rod photoreceptor bright-flash responses.

Highlights

Vertebrate phototransduction has been studied extensively since the 1970s, and a number of quantitative molecular models have been developed that have provided a good description of many features of the rod’s electrical response to light (e.g. [1,2,3,4,5,6,7,8])
We standardized on a G-protein activation rate of νG* = 1250 s−1 because this provided a good description of the transition intensity between dominant time constants in the bright-flash regime
We have presented an updated model of rod phototransduction, based on the recent evidence that activation of the dimeric PDE6 requires the binding of two molecules of transducin [10], and we have evaluated the model’s predictions for the form of the rod’s electrical response to bright flashes of light

Summary

Introduction

Vertebrate phototransduction has been studied extensively since the 1970s, and a number of quantitative molecular models have been developed that have provided a good description of many features of the rod’s electrical response to light (e.g. [1,2,3,4,5,6,7,8]). Vertebrate phototransduction has been studied extensively since the 1970s, and a number of quantitative molecular models have been developed that have provided a good description of many features of the rod’s electrical response to light We contend that each of these models suffers important shortcomings, which we enumerate below In light of these issues, we have developed a new quantitative model of vertebrate phototransduction, and we have investigated its applicability to the electrical responses of mammalian rods to bright flashes of light. We suggest that the most serious shortcoming in previous quantitative descriptions of the vertebrate phototransduction cascade is that they have invariably overlooked the dimeric nature of the activation of the PDE6 by transducin, as originally reported decades ago [9], and recently re-examined [10,11]. Our recent examination of the implications of dimeric activation [11] and our further analysis in this paper have shown that the ‘independent activation’ simplification can lead to errors in the predicted kinetics of both activation and shut-off of the light response

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Discussion

Conclusion