We evaluated the generality of two models of vertebrate
phototransduction. The approach was to quantitatively optimize
each model to the full waveform of high-quality, dark-adapted
(DA), salamander rod flash responses. With the optimal
parameters, each model was then used to account for signature,
qualitative features of rod responses from three experimental
paradigms (stimulus/response, “S/R suite”):
(1) step responses; (2) the intensity dependence of the period
of photocurrent saturation (Tsatvs. ln(I)); and (3) light-adapted (LA)
incremental flash sensitivity as a function of background
intensity. The first model was the recent successful model
of Nikonov et al. (1998). The second model replaced the
instantaneous Ca2+ buffering used in the Nikonov
et al. model with a dynamic buffer. The results showed
that, in the absence of the dynamic Ca2+ buffer,
the Nikonov et al. model does not have sufficient flexibility
to provide a good fit to the flash responses, and,
using the same parameters, reproduce the salient features
of the S/R suite—critical features at step onset and
offset are absent; the Tsat function
has too shallow a slope; and the model cannot generate the
empirically observed I-range of Weber–Fechner
LA behavior. Some features could be recovered by changing
parameters, but only at the expense of the fit to the reference
(Ref) data. When the dynamic buffer is added, the model
is able to achieve an acceptable fit to the Ref data
while reproducing several features of the S/R suite, including
an empirically observed Tsat
function, and an extended range of LA flash sensitivity
adhering to Weber's law. The overall improved behavior
of the model with a dynamic Ca2+ buffer indicates
that it is an important mechanism to include in a working
model of phototransduction, and that, despite the slow
kinetics of amphibian rods, Ca2+ buffering should
not be simulated as an instantaneous process. However,
neither model was able to capture all the features with
the same parameters yielding the optimal fit to the Ref
data. In addition, neither model could maintain a good
fit to the Ref data when five key biochemical parameters
were held at their current known values. Moreover, even
after optimization, a number of important parameters remained
outside their empirical estimates. We conclude that other
mechanisms will need to be added, including additional
Ca2+-feedback mechanisms. The present research
illustrates the importance of a hybrid qualitative/quantitative
approach to model development, and the limitations of modeling
restricted sets of data.
In Silico Modelling of Transdermal and Systemic Kinetics of Topically Applied Solutes: Model Development and Initial Validation for Transdermal Nicotine
