Introduction 
The essential morphological features of neu- 
rons were established in the 1870s and 1880s, 
with the aid of a number of selective staining pro- 
cedures, notably the metallic impregnation tech- 
nique developed by the Italian microscopist Ca- 
millo Golgi. And the fundamental principle of 
the neuron doctrine, namely, that nerve cells are 
anatomically and functionally discrete entities, 
was convincingly demonstrated around the turn 
of the century by the great Spanish neurohistolo- 
gist, Santiago Ramon y Cajal. The biophysical 
mechanisms responsible for the nerve impulse 
and for synaptic transmission were established in 
the early 1950s, principally through the work of 
Hodgkin, Huxley, Katz, and Eccles (Figures 21, 
22, and 23). In brief, activation of a nerve cell 
results in the successive opening of pores or ion 
channels along the length of the axon that result 
in the temporary reversal of the voltage between 
the inside and the outside of the axon (this tran- 
sient change in potential is the action potential; 
see Figure 7) . When the action potential reaches 
the ends of the axon it causes the release of a 
neurotransmitter that diffuses across the micro- 
scopic gap between the axon terminal and the 
postsynaptic cell. The binding of the neurotrans- 
mitter to specialized receptors in the membrane 
of the postsynaptic cell in turn triggers a response 
in that cell which may either be the opening of an 
ion channel or the activation of a second intracel- 
lular messenger in the cell. In either case the 
binding of the transmitter to the receptor is re- 
flected in the generation of a graded voltage 
change across the membrane of the postsynaptic 
cell, called a synaptic potential. Depending on 
the nature of the transmitter receptor, the re- 
sponse may be either excitatory or inhibitory; 
i.e., the postsynaptic cell may either be activated 
or rendered less likely to discharge an impulse. 
Finally, the released neurotransmitter is either 
broken down by a specific enzyme within the 
synaptic cleft, or taken up by selective transport 
mechanisms into the axon terminal (where it can 
be reutilized) or into the surrounding nonneural 
(glial) cells. 
In the past 10 years we have learned a good 
deal about the molecular mechanisms involved 
in both impulse conduction and synaptic trans- 
mission, largely as the result of the successful 
cloning of the genes for a number of the ion chan- 
nels involved (e.g., for Na"*^, K^, and Ca^"^) and for 
many neurotransmitter receptors like those for 
acetylcholine, glutamate, 7-aminobutyric acid 
(GABA), serotonin, norepinephrine, dopamine. 
and various peptides. From the nucleotide se- 
quence of these genes it has been possible not 
only to deduce the primary amino acid sequence 
of the channel or transmitter proteins (and from 
this to infer the probable arrangement of the rele- 
vant protein in the membrane) but also to gener- 
ate hybridization probes to identify other related 
channels or receptors. And using some of the es- 
tablished techniques of genetic engineering, like 
site-directed mutagenesis, it has been possible in 
some cases to establish the regions within the 
channel molecules that are sensitive to changes 
in voltage (Figure 24), or the ligand-binding and 
second messenger-activating domains of recep- 
tors. One example will suffice to demonstrate the 
importance of this approach to our understand- 
ing of these fundamental processes. 
It has been known for almost 50 years that the 
relatively simple molecule acetylcholine is the 
transmitter at the junctional region between mo- 
tor nerve fibers and muscle cells and also at cer- 
tain synapses in the brain and spinal cord. With 
the discovery in the 1970s that the clinical con- 
dition myasthenia gravis (previously discussed 
in the immunology section) is caused by circulat- 
ing antibodies directed against the receptor for 
acetylcholine in the muscle membrane, a major 
effort was mounted to purify and biochemically 
characterize the acetylcholine receptor (AChR) . 
This work served to establish that the AChR con- 
sists of five subunits: two designated a, and one 
each called ^, 7, and b. 
In the early 1980s Heinemann, Patrick, and 
their colleagues succeeded in cloning the genes 
for the a-subunit, and in 1983 Numa and his co- 
workers presented the complete nucleotide se- 
quences encoding all four kinds of subunits. 
From these sequences we gained several impor- 
tant insights. First, the four subunits showed a 
high degree of homology, which suggested that 
their genes were probably derived — by duplica- 
tion and divergence — from a single ancestral 
gene. Second, the similarities in the predicted 
amino acid sequences suggested that the subunits 
are probably arranged to form a central pore or 
channel between them. Third, the presence in 
each subunit of four hydrophobic regions, each 
about 20 amino acids long, immediately sug- 
gested the probable disposition of the subunits, 
with four transmembrane domains (Ml, M2, M3, 
and M4) and intervening intra- and extracellular 
linking segments. More recent work has identi- 
fied a fifth subunit type f and has established the 
precise location of the acetylcholine-binding site 
