BIOPHYSICAL THEORY AND MODELING |
Modeling the Role of Incisures in Vertebrate Phototransduction
Giovanni Caruso 1, Paolo Bisegna 2, Lixin Shen 3, Daniele Andreucci 4, Heidi E. Hamm 3 and Emmanuele DiBenedetto 3*
1 ITC, CNR, Italy
2 University of Rome Tor Vergata, Italy
3 Vanderbilt University
4 University of Rome La Sapienza, Italy
* To whom correspondence should be addressed. E-mail: em.diben{at}vanderbilt.edu.
Submitted on February 17, 2006
Revised on April 22, 2006
Accepted on 8 May 2006
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Abstract |
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Phototransduction is mediated by a G protein-coupled receptor-mediated cascade, activated by light and localized to rod outer segment (ROS) disc membranes, which, in turn, drives a diffusion process of the second messengers cGMP and Ca2+ in the ROS cytosol. This process is hindered by discs, which, however, bear physical cracks, known as incisures, believed to favor the longitudinal diffusion of cGMP and Ca2+.
This paper is aimed at highlighting the biophysical functional role and significance of incisures, and their effect on the local and global response of the photocurrent. Previous work on this topic (e.g., (1) and (2)), regarded the ROS as "well stirred" in the radial variables, lumped the diffusion mechanism on the longitudinal axis of the ROS, and replaced the cytosolic diffusion coefficients by "effective" ones, accounting for incisures through their total patent area only. The fully spatially resolved model recently published by our group (3), is a natural tool to take into account other significant details of incisures, including their geometry and distribution.
Using mathematical theories of homogenization and concentrated capacity, it is shown here that the complex diffusion process undergone by the second messengers cGMP and Ca2+ in the ROS bearing incisures can be modeled by a family of 2-dimensional diffusion processes on the ROS cross sections, "glued" together by other 2-dimensional diffusion processes, accounting for diffusion in the ROS outer shell and in the blade-like regions comprised by the stack of incisures.
Based on this mathematical model, a code has been written, capable of incorporating an arbitrary number of incisures and activation sites, with any given arbitrary distribution within the ROS. The code is aimed at being an operational tool to perform numerical experiments of phototransduction, in rods with incisures of different geometry and structure, under a wide spectrum of operating conditions.
The simulation results show that incisures have a dual biophysical function. On one hand, since incisures line up from disc to disc, they create vertical cytoplasmic channels crossing the discs, thus facilitating diffusion of second messengers. On the other hand, at least in those species bearing multiple incisures, they divide the discs into lobes like the petals of a flower, thus confining the diffusion of activated phosphodiesterase and localizing the photon response. Accordingly, not only the total area of incisures, but also their geometrical shape and distribution significatively influence the global photoresponse.
Key Words:
computer simulation, mathematical model, molecular dynamics, photoreceptor cell, second messenger, signal transduction
