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Newbie seeks advice in modeling NMDA-channel

Matt Jones jonesmat at ohsu.edu
Thu Nov 4 15:14:53 EST 1999


In article <19991104165359229443 at nafp2-035.rz.uni-frankfurt.de> Melvin,
cwilms at stud.uni-frankfurt.de writes:
>I have decided to go with the differential equations, since that was teh
>direction I was thinking of anyway and simply because that gives me a
>realistic chance of getting done on time. I find the thoughts behind the
>Monte Carlo-method intresting, but will look into that later.
>
>Right now I am trying to figure out, if a Maple-Programm wouldn't be
>better, than a "real" program done in some OOP-language.
>

Smart choice from the "getting something running immediately" point of
view. I'm not very familiar with Maple, but I gather that it's a symbolic
algebra and calculus program, and you should therefore be able to stick
together differential equations and get exact solutions relatively
easily, or failing that, should be able to get numerical approximations
that are "close enough for government work" as we say over here.

Regardless of whether you want to do it symbolically or numerically, I
strongly recommend looking at the chapters by Colquhoun and Hawkes in the
Single Channel Recording book (eds. Sakmann and Neher).  These, and their
series of Proc. Roy. Soc. papers on stochastic channel analysis,  are the
definitive works and contain appendices with APL (sp?) code for writing a
Q-Matrix program (I believe this is the calculus library that Maple is
based on).  

If I recall, the first chapter in the Koch book also has specific info
about NMDA channel modeling. But the models don't contain desensitized
states (which comprise a large chunck of the experimental literature),
and were constrained just by fitting the time course of NMDA EPSCs. This
is a good place to start, but will not allow you to get close to a unique
set of rate constants. That is, there are lots of different combinations
of rate constants and model structures that will give currents similar in
shape to EPSCs, whereas how these channels function at synapses may (or
may not...) depend strongly on kinetics that are not obvious just from
the shape of the EPSC. Additional kinetic data from patch experiments can
further constrain the model into a smaller subset of acceptable choices. 
Again, the Lester and Jahr paper has a model constrained by lots of
different experimental protocols: paired-pulses,  agonists with different
binding and unbinding kinetics, short and long pulses emphasizing
deactivation and desensitization respectively, etc.  Also, for drug
kinetics, check out papers from the labs of Craig Jahr and Gary Westbrook
(MK-801) and from that of Mark Mayer (various antagonists and agonists,
and a very interesting voltage-dependent channel blocker
9-aminoacridine). 

Cheers,

Matt Jones




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