Xref: utzoo sci.bio:846 sci.med:3945
Path: utzoo!mnetor!uunet!munnari!otc!metro!physiol!daved
From: daved@physiol.su.oz (Dave Davey)
Newsgroups: sci.bio,sci.med
Subject: Re: Acetylcholine source needed...
Message-ID: <150@physiol.su.oz>
Date: 20 Jan 88 01:06:42 GMT
References: <506@dl901b.engin.umich.edu> <560@spdcc.COM> <1559@aecom.YU.EDU>
Organization: Physiology Dept., Univ. of Sydney, NSW, Australia
Lines: 42
Summary: acetylcholineserase does not increase nerve terminal acetlycholine

In article <1559@aecom.YU.EDU>, werner@aecom.YU.EDU (Craig Werner) writes:
> 	Of course, there are drugs that increase acetylcholine in the
> nerve terminals: Edrophonium, Neostigmine, and other Acetylcholinesterase
> inhibitors.
These inhibitors act on acetylcholinesterase, an enzyme which breaks 
down acetylcholine, the chemical transmitter released by some nerve 
terminals, notably those activating skeletal muscle cells, into its 
constituent choline and acetate, neither of which have appreciable 
affects on the receptor molecules.  At the neuromuscular junction, the 
enzyme is present in the gaps between each nerve terminal and muscle 
cell in very significant amounts.  This appears paradoxical, but makes 
it possible for a large amount of acetylcholine to be released, 
ensuring rapid and complete activation of the muscle cell involved, 
without lengthy activation that would otherwise occur.  The result is 
that normal neuromuscular junctions can both transmit impulses very 
reliably, and achieve much higher frequencies than would otherwise be 
possible.  The overall mechanism consumes more acetylcholine than would 
be required if the enzyme were absent but the added advantage of speed 
and reliability must have conferred a sufficient advantage in a world 
of predators and prey to have been genetically advantageous.  

Blocking the cholinesterase can augment the amount of acetylcholine 
which reaches the receptors, and greatly lengthen the time over which 
it may do so.  At a normal neuromuscular junction, this can be very 
detrimental.  At low doses, muscle responses will be accentuated and 
prolonged, but at higher doses a property of the receptor known as 
"desensitisation" comes into play.  The prolonged presence of the 
transmitter causes the receptor response to fail, and the 
neuromuscular junction is "blocked"; the muscle cells are "paralysed".  
The low dose effect is useful in the treatment of conditions in which 
an abnormally small amount of acetylcholine is released (and is 
probably responsible for the uncontrolled wing motion in insects 
poisoned with anticholinesterases.)  The paralytic effect is at the
heart of the action of the class of "depolarising blocking agents" used
in surgery, but that's another story...

It is unlikely that blocking the destructive action of the enzyme 
would cause an increased amount of acetylcholine in the nerve 
terminal.  A feedback mechanism would probably cause the reverse; the 
terminal can (and must) transport choline from the intercellular gap 
mentioned above into the terminal, but probably does not transport 
acetylcholine itself.