The phototransduction cascade is paradigmatic for signaling pathways initiated by G protein-coupled receptors and is characterized by a fine regulation of photoreceptor sensitivity and electrical response to a broad range of light stimuli. Here, we present a biochemically comprehensive model of phototransduction in mouse rods based on a hybrid stochastic and deterministic mathematical framework, and a quantitatively accurate description of the rod impedance in the dark. The latter, combined with novel patch clamp recordings from rod outer segments, enables the interconversion of dim flash responses between photovoltage and photocurrent and thus direct comparison with the simulations. The model reproduces the salient features of the experimental photoresponses at very dim and bright stimuli, for both normal photoreceptors and those with genetically modified cascade components. Our modelling approach recapitulates a number of recent findings in vertebrate phototransduction. First, our results are in line with the recently established requirement of dimeric activation of PDE6 by transducin and further show that such conditions can be fulfilled at the expense of a significant excess of G protein activated by rhodopsin. Secondly, simulations suggest a crucial role of the recoverin-mediated Ca2+-feedback on rhodopsin kinase in accelerating the shutoff, when light flashes are delivered in the presence of a light background. Finally, stochastic simulations suggest that transient complexes between dark rhodopsin and transducin formed prior to light stimulation increase the reproducibility of single photon responses. Current limitations of the model are likely associated with the yet unknown mechanisms governing the shutoff of the cascade.

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

Asteriti, Sabrina;Dell'Orco, Daniele
2021

Abstract

The phototransduction cascade is paradigmatic for signaling pathways initiated by G protein-coupled receptors and is characterized by a fine regulation of photoreceptor sensitivity and electrical response to a broad range of light stimuli. Here, we present a biochemically comprehensive model of phototransduction in mouse rods based on a hybrid stochastic and deterministic mathematical framework, and a quantitatively accurate description of the rod impedance in the dark. The latter, combined with novel patch clamp recordings from rod outer segments, enables the interconversion of dim flash responses between photovoltage and photocurrent and thus direct comparison with the simulations. The model reproduces the salient features of the experimental photoresponses at very dim and bright stimuli, for both normal photoreceptors and those with genetically modified cascade components. Our modelling approach recapitulates a number of recent findings in vertebrate phototransduction. First, our results are in line with the recently established requirement of dimeric activation of PDE6 by transducin and further show that such conditions can be fulfilled at the expense of a significant excess of G protein activated by rhodopsin. Secondly, simulations suggest a crucial role of the recoverin-mediated Ca2+-feedback on rhodopsin kinase in accelerating the shutoff, when light flashes are delivered in the presence of a light background. Finally, stochastic simulations suggest that transient complexes between dark rhodopsin and transducin formed prior to light stimulation increase the reproducibility of single photon responses. Current limitations of the model are likely associated with the yet unknown mechanisms governing the shutoff of the cascade.
ADP, adenosine diphosphate
ATP, adenosine-5′-triphosphate
Arr, arrestin
BG, background illumination
CNG, cyclic nucleotide-gated (channel)
CSM, completely substituted mutant of rhodopsin
CV, coefficient of variation
DM, deterministic model
Dynamic modeling
E, effector of the phototransduction cascade, activated PDE
FFT, fast Fourier-transform
GC, guanylate cyclase
GCAPs, guanylate cyclase-activating proteins
GDP, guanosine-5′-diphosphate
GPCR, G protein-coupled receptor
GTP, guanosine-5′-triphosphate
Gt, G protein/transducin
Gα, α-subunit of the G protein
Gβγ, β- and γ-subunit of the G protein
HSDM, hybrid stochastic/deterministic model
Light adaptation
MPR, multiple photon response
PDE, phosphodiesterase 6
Ph, photons
Phototransduction
R, rhodopsin
RGS, regulator of G protein signaling
RK, rhodopsin kinase
ROS, rod outer segment
Rec, recoverin
Rn, activated rhodopsin that has been phosphorylated n times
SD, standard deviation
SPR, single photon response
Stochastic simulation
Systems biology
TTP, time to peak
cGMP, cyclic guanosine monophosphate
ΔJ, photocurrent
ΔU, photovoltage
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11562/1047031
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