Recently, we introduced a phototransduction model that was able to
account for the reproducibility of vertebrate rod single-photon responses
(SPRs) (Hamer et al., 2003). The model was able
to reproduce SPR statistics by means of stochastic activation and
inactivation of rhodopsin (R*), transducin (Gα), and
phosphodiesterase (PDE). The features needed to capture the SPR statistics
were (1) multiple steps of R* inactivation by means of multiple
phosphorylations (followed by arrestin capping) and (2) phosphorylation
dependence of the affinity between R* and the three molecules competing to
bind with R* (Gα, arrestin, and rhodopsin kinase). The
model was also able to account for several other rod response features in
the dim-flash regime, including SPRs obtained from rods in which various
elements of the cascade have been genetically disabled or disrupted.
However, the model was not tested under high light-level conditions. We
sought to evaluate the extent to which the multiple phosphorylation model
could simultaneously account for single-photon response behavior, as well
as responses to high light levels causing complete response saturation
and/or significant light adaptation (LA). To date no single model,
with one set of parameters, has been able to do this. Dim-flash responses
and statistics were simulated using a hybrid stochastic/deterministic
model and Monte-Carlo methods as in Hamer et al. (2003). A dark-adapted flash series, and stimulus
paradigms from the literature eliciting various degrees of light
adaptation (LA), were simulated using a full differential equation version
of the model that included the addition of Ca2+-feedback onto
rhodopsin kinase via recoverin. With this model, using a single
set of parameters, we attempted to account for (1) SPR waveforms and
statistics (as in Hamer et al., 2003); (2) a
full dark-adapted flash-response series, from dim flash to saturating,
bright flash levels, from a toad rod; (3) steady-state LA responses,
including LA circulating current (as in Koutalos et
al., 1995) and LA flash sensitivity measured in rods from four
species; (4) step responses from newt rods (Forti et
al., 1989) over a large dynamic range; (5) dynamic LA responses,
such as the step-flash paradigm of Fain et al. (1989), and the two-flash paradigm of Murnick and Lamb
(1996); and (6) the salient response features
from four knockout rod preparations. The model was able to meet this
stringent test, accounting for almost all the salient qualitative, and
many quantitative features, of the responses across this broad array of
stimulus conditions, including SPR reproducibility. The model promises to
be useful in testing hypotheses regarding both normal and abnormal
photoreceptor function, and is a good starting point for development of a
full-range model of cone phototransduction. Informative limitations of the
model are also discussed.