Network-level analysis of light adaptation in rod cells under normal and altered conditions

Abstract

Photoreceptor cells finely adjust their sensitivity and electrical response according to changes in light stimuli as a direct consequence of the feedback and regulation mechanisms in the phototransduction cascade. In this study, we employed a systems biology approach to develop a dynamic model of vertebrate rod phototransduction that accounts for the details of the underlying biochemistry. Following a bottom-up strategy, we first reproduced the results of a robust model developed by Hamer et al. (Vis. Neurosci., 2005, 22(4), 417), and then added a number of additional cascade reactions including: (a) explicit reactions to simulate the interaction between the activated effector and the regulator of G-protein signalling (RGS); (b) a reaction for the reformation of the G-protein from separate subunits; (c) a reaction for rhodopsin (R) reconstitution from the association of the opsin apoprotein with the 11-cis-retinal chromophore; (d) reactions for the slow activation of the cascade by opsin. The extended network structure successfully reproduced a number of experimental conditions that were inaccessible to prior models. With a single set of parameters the model was able to predict qualitative and quantitative features of rod photoresponses to light stimuli ranging over five orders of magnitude, in normal and altered conditions, including genetic manipulations of the cascade components. In particular, the model reproduced the salient dynamic features of the rod from Rpe65(-/-) animals, a well established model for Leber congenital amaurosis and vitamin A deficiency. The results of this study suggest that a systems-level approach can help to unravel the adaptation mechanisms in normal and in disease-associated conditions on a molecular basis.

Calcium binding, structural stability and guanylate cyclase activation in GCAP1 variants associated with human cone dystrophy

“…Gathering detailed biochemical and biophysical information on the molecular determinants of disease-associated states is essential in order to be able to quantitatively describe phototransduction events in normal and altered conditions, and hence to design effective interventions [6]. In this study we attempted to characterize the effects of Ca 2?…”

“…Ca 2? /GCAP-dependent regulation of ROS-GC activity forms a powerful feedback mechanism that sets the overall photoresponse and is highly involved in adaptation phenomena [5,6]. Among GCAPs, GCAP1 shows stronger immunoreactivity in cones than in rods [7] and was found to be capable of restoring recovery of rod and cone photoresponses in the absence of GCAP2 [3,8].…”

Exploring the rate-limiting steps in visual phototransduction recovery by bottom-up kinetic modeling

“…As perhaps one of the best-understood GPCR-mediated signaling pathways, the phototransduction system has seen a rich history of modeling. This has led to comprehensive models of the amphibian phototransduction cascade, which include a large portion of the known reactions that occur during phototransduction [1,13-15]. Despite the intrinsic limits brought in by the well-stirred approximation, such comprehensive models have proven realistic and widely useful.…”

“…[16]) and in unraveling some molecular mechanisms associated to disease (ref. [15]). Different modeling approaches account for spatial dynamics of the processes occurring in specific cell compartments [17,18].…”

A Calcium-Relay Mechanism in Vertebrate Phototransduction

“…The output consists of the simulated time course of the photocurrents, which can be compared with experimental electrophysiological recordings. 55 The modular nature of the model allows the insertion of new mechanisms and the quantitative effects on the overall network can thus be directly assessed. 56,57 In such a framework, the addition of the Ca 2+ -relay model can be realized by assuming that the rate of cGMP synthesis by ROS-GC1 is regulated by both GCAP1 and GCAP2 as follows: where a max = 60 μM/s 45 is the maximal activation of GC1, assumed to be the same for both GCAP1 and GCAP2, [Ca 2+ free ] is the free intracellular calcium depending on the illumination level, and IC 50 (139 nM and 59 nM 34 ) and m (1.7 and 2.4 32 ) indicate, respectively, the free Ca…”