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Information Regarding PNTModel Version 1.0
Date: December 20, 2007
Written by R. S. Bain
Carleton University
Ottawa, Canada
Description
The simulation represents the cascade of interactions that leads to
docking and fusion of synaptic vesicles at a presynaptic nerve terminal.
For background regarding the biochemistry, the references given in
the supporting document represent a few of the better-known articles
in the field.
The biological objective of the cascade is to transmit nerve impulses from
one nerve cell (neuron) to another. In simplified form this is achieved by
1. Arrival of an impulse (action potential) at the nerve terminal.
2. Opening of calcium ion channels.
3. Activation of the protein calmodulin (CaM) by the calcium ions.
4. Activation of calcium-calmodulin dependent protein kinase II (CaMKII) by having an activated CaM bind to it.
5. Phosphorylation of synapsin which is a protein that binds vesicles in clusters. Phosphorylation is the
addition of a phosphate group. When phosphorylated, synapsins lose most of their affinity for vesicles.
This allows the vesicles to move to the active zone.
6. Docking of vesicles at the active zone.
7. Fusion of vesicles with the active zone which releases the chemical neurotransmitter within them. This
neurotransmitter is detected by neighboring neurons and action potentials are started in them.
Key Features In Terms Of Cell-DEVS Modelling
In terms of implementing models using Cell-DEVS with CD++ here is a list of features
of the model. This does not imply that how the following were implemented is the best
way to do this.
1. Extensive use of macros.
2. Multiple layers.
3. Use of the time function to schedule events.
4. Particles in motion that collide and bounce off each other.
5. Interactions between particles where one affects the state of the other.
6. Interactions between particles where two join to become one complex.
For background, the bouncing ball simulation is a good place to start to see
how to create a particle in motion. The idea of the calcium spreading is similar
to the 2-d heat diffusion model.
What You See In the Simulation
The initial setup contains fluid and particles within a nerve terminal. The colours
represent different types of cells:
Black cell membrane
Red active zone
Rose calcium ion channels (two cell near active zone)
Orange calmodulin (CaM)
Green calcium-calmodulin activated protein kinase II (CaMKII)
Cyan synapsin
Violet synaptic vesicles
When the simulation starts, the CaM and CaMKII move about within the terminal. There is
no interaction between any particles. After a short time the action potential arrives. This
changes the cell membrane colour to yellow. This is for visual effect only. Nothing else
changes until the calcium ion channels open.
There is a time lag after the action potential arrives until the calcium ion channels open
(they change colour). In real cells this allows calcium ions to enter the cell, but here it just
signifies that calcium ions are to be created in the cells adjacent to the channels. You
will not see this in the animation: the calcium is created on layer 2 so the cells in the main
layer have to check layer 2 to see if there is calcium there.
There are two vesicles already docked at the active zone. They require calcium to fuse, so
you will see one vesicle disappear quickly when the channels are opened.
The calcium ions activate the CaM. Visually this means that the CaM turns dark orange. You
will see the CaMs near the channels turn dark orange first.
When an activated CaM bumps into a CaMKII it may combine with it to form a complex. If this
does occur, the CaMKII will turn a darker green and the activated CaM will disappear.
Now, if the activated CaMKII bumps into a synapsin it may phosphorylate it. This will result in
the synapsin changing colour to dark blue and becoming mobile.
When a vesicle is no longer next to any stationary synapsins, it too becomes mobile. It then goes
towards the active zone and docks.
The movement of vesicles has priority over the other particles and the rules for its path are
structured so as to encourage it to head to the active zone.
Summary
calcium changes CaM from light to dark orange
CaM combines with CaMKII and changes it to dark green
CaMKII phosphorylates synapsin and changes it from cyan to dark blue
vesicles become mobile when not attached to any synapsins and drift toward active zone