Kinetics of Rhodopsin Deactivation and Its Role in Regulating Recovery and Reproducibility of Rod Photoresponse

Caruso, Giovanni; Bisegna, Paolo; Lenoci, Leonardo; Andreucci, Daniele; Gurevich, Vsevolod V.; Hamm, Heidi E.; DiBenedetto, Emmanuele

doi:10.1371/journal.pcbi.1001031

Cited by 23 publications

(56 citation statements)

References 47 publications

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“…A more detailed comparison between virtual and experimental data is in ref. 10. However, often an explanation of variability suppression is provided in terms of the variability of the activated complex E Ã and the number of steps to R Ã deactivation (2,4,7,16).…”

Section: Resultsmentioning

confidence: 99%

“…10 and 13, simulates several components of the SPR. These include the stochastic effects of the activation/deactivation cascade (10), and biophysical and electrophysiological processes taking place in the transduction part of the cascade. Among these are the effects of sophisticated ROS geometry, the diffusion of the second messengers cGMP, and Ca 2þ in the cytoplasm, and their role in generating the photocurrent with high coopera- tivity.…”

Section: Methodsmentioning

confidence: 99%

“…The first is by the CV of the activated effector E Ã (not experimentally accessible in intact rods), and the second is by the CV of the photocurrent [the output of the system that can be experimentally measured (2-4), downstream of the transduction process]. The first bears the random elements of the deactivation cascade (10), and the second is mitigated by the cytoplasm, the physical medium where the second messengers diffuse (9). The stochastic and biochemical aspects of R Ã deactivation are described in (10).…”

Section: Methodsmentioning

confidence: 99%

“…The first bears the random elements of the deactivation cascade (10), and the second is mitigated by the cytoplasm, the physical medium where the second messengers diffuse (9). The stochastic and biochemical aspects of R Ã deactivation are described in (10). The technical aspect of the nonlinear couplings between second messengers and current and Ca 2þ feedback are explained in refs.…”

Section: Methodsmentioning

confidence: 99%

“…For example the CV of the peak current amplitudes in toad is reported to be about 20% (5), and for a mouse, the CV of the area integral (integral of the relative current suppression, over the whole time course of the phenomenon), is about 36% (4). The mechanisms that ensure such a low variability of the SPR are not completely understood, and are the object of current experimental and theoretical investigation (2)(3)(4)(5)(6)(7)(8)(9)(10).…”

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confidence: 99%

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Identification of key factors that reduce the variability of the single photon response

Caruso

Bisegna

Andreucci

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Rod photoreceptors mediate vision in dim light. Their biological function is to discriminate between distinct, very low levels of illumination, i.e., they serve as reliable photon counters. This role requires high reproducibility of the response to a particular number of photons. Indeed, single photon responses demonstrate unexpected low variability, despite the stochastic nature of the individual steps in the transduction cascade. We analyzed individual system mechanisms to identify their contribution to variability suppression. These include: (i) cooperativity of the regulation of the second messengers; (ii) diffusion of cGMP and Ca 2þ in the cytoplasm; and (iii) the effect of highly localized cGMP hydrolysis by activated phosphodiesterase resulting in local saturation. We find that (i) the nonlinear relationships between second messengers and current at the plasma membrane, and the cGMP hydrolysis saturation effects, play a major role in stabilizing the system; (ii) the presence of a physical space where the second messengers move by Brownian motion contributes to stabilization of the photoresponse; and (iii) keeping Ca 2þ at its dark level has only a minor effect on the variability of the system. The effects of diffusion, nonlinearity, and saturation synergize in reducing variability, supporting the notion that the observed high fidelity of the photoresponse is the result of global system function of phototransduction.modeling | rhodopsin | deactivation | phosphorylation I n vertebrate retinal rod photoreceptors, light-activated rhodopsin R Ã activates dozens of G proteins (T → T Ã ) during its random lifetime, by catalyzing GDP/GTP exchange on the G protein α-subunit. Each T Ã molecule associates, one-to-one, with a catalytic subunit of the effector, forming an active T Ã -E complex, denoted by E Ã . Molecules of E Ã hydrolyze the second messenger, cGMP. Reduction of the cGMP level induces its dissociation from the cGMP-gated cation channels, causing channel closure and suppression of the inward current. This current suppression is the experimentally measured electrophysiological response, which is usually normalized by the dark current j dark , yielding the relative current suppression (1)The mechanism of R Ã deactivation contains several random components, including the random number of phosphorylations by rhodopsin kinase (RK), and the random sojourn time at each phosphorylation level. These steps regulate the number of generated E Ã molecules and, hence, the response. Because of this randomness the responses are expected to be inherently variable, in the sense that any two rhodopsin photoisomerizations yield different responses. The system would be stable if these responses are statistically close. A measure of stability is the coefficient of variation (CV), defined as the ratio of the standard deviation to the mean, calculated over a large number of signaling events and their corresponding responses. However, the measured single photon response (SPR) is highly reproducible, i.e., the coefficient of var...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Identification of key factors that reduce the variability of the single photon response

Caruso

Bisegna

Andreucci

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Mathematical Modeling of the Rod Phototransduction Process

Caruso

2021

Harnack Inequalities and Nonlinear Operators

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Analysis of dim-light responses in rod and cone photoreceptors with altered calcium kinetics

Abtout,

Reingruber

2023

J. Math. Biol.

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Rod and cone photoreceptors in the retina of vertebrates are the primary sensory neurons underlying vision. They convert light into an electrical current using a signal transduction pathway that depends on Ca$$^{2+}$$ 2 + feedback. It is known that manipulating the Ca$$^{2+}$$ 2 + kinetics affects the response shape and the photoreceptor sensitivity, but a precise quantification of these effects remains unclear. We have approached this task in mouse retina by combining numerical simulations with mathematical analysis. We consider a parsimonious phototransduction model that incorporates negative Ca$$^{2+}$$ 2 + feedback onto the synthesis of cyclic GMP, and fast buffering reactions to alter the Ca$$^{2+}$$ 2 + kinetics. We derive analytic results for the photoreceptor functioning in sufficiently dim light conditions depending on the photoreceptor type. We exploit these results to obtain conceptual and quantitative insight into how response waveform and amplitude depend on the underlying biophysical processes and the Ca$$^{2+}$$ 2 + feedback. With a low amount of buffering, the Ca$$^{2+}$$ 2 + concentration changes in proportion to the current, and responses to flashes of light are monophasic. With more buffering, the change in the Ca$$^{2+}$$ 2 + concentration becomes delayed with respect to the current, which gives rise to a damped oscillation and a biphasic waveform. This shows that biphasic responses are not necessarily a manifestation of slow buffering reactions. We obtain analytic approximations for the peak flash amplitude as a function of the light intensity, which shows how the photoreceptor sensitivity depends on the biophysical parameters. Finally, we study how changing the extracellular Ca$$^{2+}$$ 2 + concentration affects the response.

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Kinetics of Rhodopsin Deactivation and Its Role in Regulating Recovery and Reproducibility of Rod Photoresponse

Cited by 23 publications

References 47 publications

Identification of key factors that reduce the variability of the single photon response

Identification of key factors that reduce the variability of the single photon response

Mathematical Modeling of the Rod Phototransduction Process

Analysis of dim-light responses in rod and cone photoreceptors with altered calcium kinetics

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