Paradoxical dose-reponse curves

Matt Jones jonesmat at ohsu.edu
Tue Sep 26 11:57:45 EST 1995


This'll be a long one, folks. Tune out now if channel kinetics bore you!

In article <drg-260995104721 at ache.pharm.pitt.edu> Duke Groebe,
drg at prophet.pharm.pitt.edu writes:
>I have some knowledge of nAChR function, though, admittedly, mostly
>investigating antagonist binding.  

Congratulations, Duke.

>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).

No, you didn't, and yes, it does. This has been shown by many authors
through analysis of single channel data, at various agonist
concentrations and membrane potentials. It produces a concentration- and
voltage-dependent increase in brief closures (blocks). Just like QX-222
and QX-314, except with a much lower affinity. Other agonists do this
too, with varying affinities. For ACh, the  affinity for the blocking
site (in the membrane electric field) is lower than that for the channel
activation binding site (maybe high up on the extracellular domain), as I
stated in my initial post. These results are reviewed in the abstract
excerpts at the end of this post (which, incidentally, took me about five
minutes to find using medline). Getting back to the original thread, this
behavior will produce bell-shaped dose-response curves under some
experimental conditions.


>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.  <snip>

Yes, this is also true. But it is an entirely different phenomenon than
open channel block by the agonist. Both desensitization and channel block
must be taken into account when applying high ACh concentrations to the
receptor. There is probably also an interaction between blocking and
desensitization, but how this is manifest will depend on the specific
kinetic mechanism of channel gating (i.e. in some models, open channel
block may delay entry into desensitized states by tying up the channel in
the blocked state). 


><snip> 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. 

Here, it is important not to confuse the desensitized and blocked
channel. They are two different things. You're right that desensitized
states have a higher affinity for ACh (simply because the exit rates from
these states are probably slow, which delays the return to the unbound
state, yielding a slower apparent dissociation constant: higher
affinity). But I think it's a bit of a semantic (or philosophical,
whichever) argument that the ACh doesn't need to remain bound for the
desensitization to persist. I wouldn't call an unbound state
desensitized, just unbound. Frankly, I think the evidence on this point
is pretty weak. I would gladly read any papers you suggest that show
otherwise. By the way, as the body is a functional thing, it's my opinion
that "function-based" studies are the best way to learn about how it
works.


>Receptor kinetics is such a funny thing.

Yea, verily.

Cheers,
-Matt 


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Excerpts from Agonist Open Channel Block papers:
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