Dynamics of mouse rod phototransduction and its sensitivity to variation of key parameters.
The deep understanding of the biochemical and biophysical basis of visual transduction, makes it ideal for systems-level analysis. A sensitivity analysis is presented for a self-consistent set of parameters involved in mouse phototransduction. The organising framework is a spatio-temporal mathematical model, which includes the geometry of the rod outer segment (ROS), the layered array of the discs, the incisures, the biochemistry of the activation/deactivation cascade and the biophysics of the diffusion of the second messengers in the cytoplasm and the closing of the cyclic guanosine monophosphate (cGMP) gated cationic channels. These modules include essentially all the relevant geometrical, biochemical and biophysical parameters. The parameters are selected from within experimental ranges, to obey basic first principles such as conservation of mass and energy fluxes. By means of the model they are compared to a large set of experimental data, providing a strikingly close match. Following isomerisation of a single rhodopsin R * (single photon response), the sensitivity analysis was carried out on the photo-response, measured both in terms of number of effector molecules produced, and photocurrent suppression, at peak time and the activation and recovery phases of the cascade. The current suppression is found to be very sensitive to variations of the catalytic activities, Hill's coefficients and hydrolysis rates and the geometry of the ROS, including size and shape of the incisures. The activated effector phosphodiesterase (PDE *) is very sensitive to variations of catalytic activity of G-protein activation and the average lifetimes of activated rhodopsin R * and PDE *; however, they are insensitive to geometry and variations of the transduction parameters. Thus the system is separated into two functional modules, activation/deactivation and transduction, each confined in different geometrical domains, communicating through the hydrolysis of cGMP by PDE *, and each sensitive to variations of parameters only in its own module.
Shen
L
L
Vanderbilt University Medical Center, Department of Pharmacology, Nashville, TN, USA.
Caruso
G
G
Bisegna
P
P
Andreucci
D
D
Gurevich
V V
VV
Hamm
H E
HE
DiBenedetto
E
E
D000818:Animals; D003198:Computer Simulation; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008027:Light; D055537:Light Signal Transduction / Q000502:physiology* / Q000528:radiation effects; D051379:Mice; D008954:Models, Biological; D012243:Rhodopsin / Q000378:metabolism*; D012374:Rod Cell Outer Segment / Q000502:physiology* / Q000528:radiation effects; D012680:Sensitivity and Specificity; D014785:Vision, Ocular / Q000502:physiology* / Q000528:radiation effects
D012243:Rhodopsin; D006152:Cyclic GMP