Paradoxical dose-reponse curves

Duke Groebe drg at prophet.pharm.pitt.edu
Tue Sep 26 09:54:36 EST 1995


> In article <4474me$76a at fremont.ohsu.edu>, you wrote:

> Can you please give more information about what is meant by
> "paradoxical"? Many drugs can give "bell-shaped" curves, where the
> response increases with dose at low concentrations, reaches a maximum,
> and then decreases at high concentrations. Simple explanations for this
> usually postulate two separate processes being induced by the same drug.
> An example is the action of ACh a nicotinic receptors. At low to moderate
> concentrations ACh activates channel opening, but at high concentrations
> it appears to block the channel, reducing current. The bell shaped curve
> probably results from the combination of a high affinity site of agonism,
> and a low affinity site for block.


.........


> In article <drg-250995144915 at ache.pharm.pitt.edu> Duke Groebe,
> drg at prophet.pharm.pitt.edu writes:
> 
> >Whoa, Matt.  I see you need to read up on nAChR function.
> 
> Duke, thank you for that extremely helpful comment.  You may also wish to
> share it with:
> 
> Sine, S.M. and Steinbach, J.H. (1984) Agonists block currents through
> acetylcholine receptor channels. Biophys. J. 46:277-284.
> 
> and 
> 
> Ogden, D.C.  and Colquhoun, D. (1985) Ion channel block by acetylcholine,
> carbachol and suberyldicholine at the frog neuromuscular junction. Proc.
> Roy. Soc. Lond. [Biol] 225:329-355. 
> 
> ...among others.

Matt,

I have some knowledge of nAChR function, though, admittedly, mostly
investigating antagonist binding.  Maybe I misinterpreted your post, but
acetylcholine (ACh), strictly speaking, does not block the channel of
nAChRs (it is not a channel blocker like QX-222 is thought to be).

Nor does ACh block channel function (by binding to the
acetylcholine-binding site) like a competitive antagonist might, like
dimethyl-d-tubocurare does.

Acetylcholine, from what I understand, blocks nicotinic receptor function
by desensitizing the receptor, i.e. causing a change in the state of the
receptor, which results in a channel which cannot pass a current.  Because
all of this binding and desensitization is, to some extent, an equilibrium
phenomenon, even at low concentrations of Ach, there are some desensitized
receptors.  Oddly enough (and in contrast to the last statement in your
original post), the desensitized (or blocked) receptor actually has a
higher affinity for acetylcholine than the resting state receptor (see,
acetylcholine does not need to be bound to a desensitized receptor in order
for the block to continue, unlike a competitive antagonist).  This is
opposite from what you might expect from function-based studies using ACh. 
Receptor kinetics is such a funny thing.

Duke

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