Structure-Based Models of NO Diffusion in the Nervous System - Computational Neuroscience: A Comprehensive Approach - page 112

4.2.4.3 Distribution of nNOS in neurons

When modelling NO formation one must know where the NOS is located and this
differs depending on the type of NOS examined. Here we are mainly concerned
with nNOS and so we should say a few words on its distribution within neurons.
In the literature nNOS is often referred to as being located on the membrane, as it
is frequently shown to be associated with postsynaptic density protein-95 (PSD-95)
which in turn is linked to the NMDA-receptor which is membrane-associated (see,
for instance [41]. This is consistent with NO acting as a retrograde messenger to
induce LTP or LTD in the pre-synaptic neuron. Thus it is natural that nNOS's po-
sition near the NMDA receptor is emphasised but this should not be taken to mean
that there is no nNOS elsewhere. Indeed, nNOS is a soluble enzyme and will be dis-
persed throughout the cytoplasm, as demonstrated by NADPH-diaphorase staining
[32]. A similar story is true of eNOS which, while it does have an affinity for the
membrane, will also be found at positions throughout the endothelial cell [11]. Thus
in our model we have made the assumption that nNOS is spread evenly within the
synthesising region with a uniform source density which we have denoted as

.

4.2.4.4 The NO threshold concentration

To quantify a threshold concentration for effective NO signalling, one first has to
specify a particular molecular signalling pathway. Here we follow the thinking of
Vaughn et al. [44] who chose the soluble guanylyl cyclase-cyclic GMP (sGC-cGMP)
signalling pathway, the major signalling pathway for NO in the brain [16, 38]. The
equilibrium dissociation constant [42] for NO for sGC is 0

. 25 µ M and this value

defines a threshold concentration for NO.

4.3 Results

In this section we apply the methods detailed above to investigate the properties of
an NO signal produced by neuron-like morphologies. In so doing, we examine a
number of salient functional questions that arise in the context of volume signalling.
In particular, we highlight the importance of the morphology of the source in deter-
mining the spatial and temporal extent of an NO volume signal. While a number of
previous models of NO diffusion in the brain have been published, they are broadly
one of two types: point-source models (see for instance [24, 47]) or compartmental
models [14, 25, 26], neither of which address the impact of the source structure on
the diffusional process. The shortcomings of these approaches are discussed in detail
in [35, 36], but we will summarise the main points here.
In a point-source model, as the name suggests, one models NO diffusing from a
source as if it were being produced at a dimensionless point at its centre. It is not
difficult to see intuitively that problems might arise from the fact that a point source