A hybrid stochastic/deterministic model of single photon response and light adaptation in mouse rods

Beelen, Charlotte Johanna; Asteriti, Sabrina; Cangiano, Lorenzo; Koch, Karl‐Wilhelm; Dell’Orco, Daniele

doi:10.1016/j.csbj.2021.06.033

Cited by 9 publications

(12 citation statements)

References 55 publications

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“…If, as postulated above, liposomes slowly release their cargo once inside the photoreceptors, a functional effect after 2-3 h may only be detectable when delivering a strongly impacting protein. Recoverin antibody could, in principle, possess such an effect, considering the crucial role of the recoverin-mediated Ca 2+ -feedback on rhodopsin kinase in accelerating the shutoff 48 . In contrast, in the present study the recombinant GCAP1 mutant had to outcompete the endogenous wild type protein An unexpected finding of this study, highly relevant for retinal disease therapy, is that intravitreal injections show extreme trial-to-trial variability in the translocation of delivered molecules to the retina.…”

Section: Discussionmentioning

confidence: 99%

Recombinant protein delivery enables modulation of the phototransduction cascade in mouse retina

Asteriti

Marino

Avesani

et al. 2022

Preprint

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Retinal dystrophies of genetic origin are often associated with mutations in the genes involved in the phototransduction cascade in photoreceptors, a paradigmatic signaling pathway mediated by G protein-coupled receptors. Photoreceptor viability is strictly dependent on the levels of the second messengers cGMP and Ca2+. Here we explored the possibility of modulating the phototransduction cascade in mouse rods using direct or liposome-mediated administration of a recombinant protein crucial for regulating the interplay of the second messengers in photoreceptor outer segments. The effects of administration of the free and liposome-encapsulated human guanylate cyclase-activating protein (GCAP1) were compared in biological systems of increasing complexity (in cyto, ex vivo, andin vivo).Analysis of protein biodistribution and direct measurement of functional alteration in rod photoresponses show that the exogenous GCAP1 protein is fully incorporated into the mouse retina and photoreceptor outer segments. Furthermore, only in the presence of a point mutation associated with cone-rod dystrophy in humans p.(E111V), protein delivery induces a disease-like electrophysiological phenotype, consistent with constitutive activation of the retinal guanylate cyclase. Our study demonstrates that both direct and liposome-mediated protein delivery are powerful tools for targeting signaling cascades in neuronal cells, which could be particularly important for the treatment of autosomal dominant genetic diseases.

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Section: Discussionmentioning

confidence: 99%

Recombinant protein delivery enables modulation of the phototransduction cascade in mouse retina

Asteriti

Marino

Avesani

et al. 2022

Preprint

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“…In this work we used a spatially well-stirred model in order to obtain analytic results that provided conceptual insight. Such models are frequently used to analyse the photoresponse [15, 31, 18, 25, 22, 23, 21, 32, 4]. Whereas spatial models are a more accurate description of reality [17, 33, 19, 20, 34], the downside is that no analytic results can usually be derived.…”

Section: Discussionmentioning

confidence: 99%

“…We used a non-spatial (well-stirred) model for the outer segment, which allowed to derive analytic results. Non-spatial models are frequently used to study the photoresponse [34, 62, 42, 41, 27, 40, 63, 58, 64, 44, 43, 36]. Whereas spatial models are a more accurate description of reality, the downside is that no analytic results can usually be derived [65, 49, 48, 46, 66, 67].…”

Section: Discussionmentioning

confidence: 99%

“…Although the phase space is now more complex, we do not expect to find solutions that are qualitatively much different from what we have observed here, which is consistent with simulations in presence of slow buffering reactions [36,37] We used a non-spatial (well-stirred) model for the outer segment, which allowed to derive analytic results. Non-spatial models are frequently used to study the photoresponse [34,62,42,41,27,40,63,58,64,44,43,36]. Whereas spatial models are a more accurate description of reality, the downside is that no analytic results can usually be derived [65,49,48,46,66,67].…”

Section: Discussionmentioning

confidence: 99%

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Analysis of calcium dynamics for dim-light responses in rod and cone photoreceptors

Abtout

Reingruber

2022

Preprint

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Rod and cone photoreceptors in vertebrate eyes are fundamental sensory neurons underlying vision. They use a sophisticated signal transduction pathway consisting of a series of biochemical processes to convert the absorption of light into an electrical response. Several of these processes are modulated by feedback mechanisms that depend on the intracellular Ca2+ concentration. In this work we use a representative phototransduction model with fast buffering to study how the Ca2+ dynamics affects the light response of mouse rod and cone photoreceptors. We obtain analytic solutions for dim-light stimulation that reveal how the dynamics of the Ca2+ concentration and the electrical current are correlated. We show how modifying the Ca2+ dynamics via buffering affects amplitude and waveform of flash and step responses. We infer that under normal physiological conditions the change in the Ca2+ concentration is proportional to the current. We show that damped oscillations appear if the Ca2+ dynamics becomes slowed down and delayed with respect to the current, e.g. through the application of buffers. We find that oscillations do not require the presence of slow buffers. We show that the phase space of the dim-light response is controlled by the ratio between the effective rate μca that controls the Ca2+ dynamics, and the dark turnover rate of cyclic GMP βd. Finally, we investigate how the light response is affected by modifying the extracellular Ca2+ concentration. In summary, we provide a comprehensive analysis that reveals how the Ca2+ dynamics affects the dim-light response in rods and cones.SignificanceThe signal transduction pathway of vertebrate rod and cone photoreceptors transforms light into an electrical response. It is regulated by several feedback processes that depend on the intracellular Ca2+ concentration. Despite of the importance of this feedback for the photoreceptor functioning, it is not well studied how modifying the Ca2+ dynamics affects the light response, for example by adding buffers. Here we derive analytic results for dim-light stimulations that provide insight into how the Ca2+ dynamics and the electrical current response are correlated. Our analysis can be used to infer properties of the Ca2+ dynamics from the observed current response, and provides insight if direct measurements of the Ca2+ dynamics in the small outer segment of a photoreceptors are not available.

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“…Differences in light sensitivity and photoresponse kinetics probably originate from different biochemical properties of rod or cone specific protein isoforms, but quantitative parameters derived from cone specific proteins are less available than those obtained with rod specific proteins ( Mustafi et al, 2009 ; Fain and Sampath, 2021 ; Kawamura and Tachibanaki, 2022 ). Biochemical and biophysical parameters based on experiments stimulated various computer assisted mathematical modeling approaches of the vertebrate photoresponse in rod outer segments ( Hamer et al, 2003 ; Dell’Orco et al, 2009 ; Invergo et al, 2013 , 2014 ; Beelen et al, 2021 ). Similar models of cone phototransduction are very limited so far, and recent attempts focus on the different morphology of rod and cone outer segments ( Klaus et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Kinetics of cone specific G-protein signaling in avian photoreceptor cells

Yee

Görtemaker

Wellpott

et al. 2023

Front. Mol. Neurosci.

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Cone photoreceptor cells of night-migratory songbirds seem to process the primary steps of two different senses, vision and magnetoreception. The molecular basis of phototransduction is a prototypical G protein-coupled receptor pathway starting with the photoexcitation of rhodopsin or cone opsin thereby activating a heterotrimeric G protein named transducin. This interaction is well understood in vertebrate rod cells, but parameter describing protein–protein interactions of cone specific proteins are rare and not available for migratory birds. European robin is a model organism for studying the orientation of birds in the earth magnetic field. Recent findings showed a link between the putative magnetoreceptor cryptochrome 4a and the cone specific G-protein of European robin. In the present work, we investigated the interaction of European robin cone specific G protein and cytoplasmic regions of long wavelength opsin. We identified the second loop in opsin connecting transmembrane regions three and four as a critical binding interface. Surface plasmon resonance studies using a synthetic peptide representing the second cytoplasmic loop and purified G protein α-subunit showed a high affinity interaction with a KD value of 21 nM. Truncation of the G protein α-subunit at the C-terminus by six amino acids slightly decreased the affinity. Our results suggest that binding of the G protein to cryptochrome can compete with the interaction of G protein and non-photoexcited long wavelength opsin. Thus, the parallel presence of two different sensory pathways in bird cone photoreceptors is reasonable under dark-adapted conditions or during illumination with short wavelengths.

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A hybrid stochastic/deterministic model of single photon response and light adaptation in mouse rods

Abstract: Graphical abstract

Cited by 9 publications

References 55 publications

Recombinant protein delivery enables modulation of the phototransduction cascade in mouse retina

Recombinant protein delivery enables modulation of the phototransduction cascade in mouse retina

Analysis of calcium dynamics for dim-light responses in rod and cone photoreceptors

Kinetics of cone specific G-protein signaling in avian photoreceptor cells

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