Nerve impulses are communicated across most synapses by small, diffusible 
molecules call neurotransmitters, such as acetylcholine(Ach) . The end of the 
presynaptic axon is filled with synaptic vesicles, each containing about 10000 Ach 
molecules. The arrival of a nerve impulse leads to the synchronous export of the 
contents of some 300 vesicles, which raises the Ach concentration in the cleft from 10 
nM to 500mM in less than a millisecond.
      The binding of Ach to the postsynaptic membrane markedly changes its ionic 
permeabilities. The conductance of both Na+ and K+ increases greatly within 0.1 msec, 
leading to a large inward current of Na+ and a smaller outward current of K+. The 
inward Na+ current depolarizes the postsynaptic membrane and triggers an action 
potential. Ach opens a single kind of cation channel, which is almost equally permeable 
to Na+ and K+. The influx of Na+ is much larger thanthe efflux of K+ because the 
electrochemical gradient across the membrane is steeper for Na+. This change in ion 
permeability is mediated by the nicotinic Ach receptor; for brevity, we shall refer to it 
as the Ach receptor. Ach also activates the muscarinic Ach receptor, which has a 
different design and function.
      The Ach receptor channel is the best-understood ligand-gated channel, and so it is 
rewarding to examine it in some detail. The electric organ of Torpedo, an electric fish, 
is a choice source because its electroplaxes (voltage-generating cells) are very rich in 
cholinergic postsynaptic membranes. The receptor is very densely packed in these 
membranes(~20,000 per mm2). Another exotic biological material has been invaluable 
in the isolation of Ach receptors. Snake neurotoxins such as a-bungarotoxin (from the 
venom of a Formosan snake) and cobratoxin block the neuromuscular transmission. 
These small (7-kd) basic proteins bind specifically and very tightly to Ach receptors 
and hence can be used as tags.
      The Ach receptor of the electric organ has been solubilized by adding a nonionic 
detergent to a postsynaptic membrane preparation and purified by affinity 
chromatography on a column bearing covalently attached cobratoxin. This 268-kd 
receptor is a pentamer of four kinds of subunits, a2bgd. Each a chain contains one 
binding site for Ach. The cloning and sequencing of the cDNAs for these subunits (50-
58 kd) showed that they have similar sequences. It seems likely that the genes for the a, 
b, g, and d subunits arose by duplication and divergence of a common ancestral gene. 
The amino-terminal half of each chain forms a hydrophilic extracellular (synaptic) 
domain. The carboxyl-terminal half, by contrast, contains four predominantly 
hydrophobic segments that span the bilayer membrane.

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